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TABLE OF CONTENTS
CHAPTER A GENERAL OVERVIEW ............................................................................... 9 SEPTEMBER
1 FOREWORD .................................................................................................................. 9
1.1 Scope of this guidance document ..................................................................... 9
1.2 Medicinal product registration ..........................................................................10
2 APPLICANT RESPONSIBILITIES .................................................................................11
3 DATA PROTECTION ....................................................................................................12
4 PATENT LINKAGE........................................................................................................13
22.2.4
Non-clinical and clinical documents .....................................................75
22.2.5
Specific documentary requirements for each evaluation route .............75
22.2.5.1 Full evaluation route ............................................................. 75 SEPTEMBER
22.2.5.2 Abridged evaluation route ..................................................... 75
22.2.5.3 Verification evaluation route.................................................. 75
23 MAV-2 SUBMISSIONS..................................................................................................76
23.1 Eligibility criteria ...............................................................................................76
23.1.1 Me-too reclassification .......................................................................77
23.2 Documentary requirements ..............................................................................77
23.2.1 Me-too reclassification .......................................................................78
LIST OF APPENDICES
APPENDIX 1 Target Processing Timelines SEPTEMBER
APPENDIX 13 Guideline on Submission for Indian Generic Products Under the CECA
Scheme
APPENDIX 16 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for Biologics
1 FOREWORD SEPTEMBER
This document should be read in conjunction with the current laws governing
pharmaceutical products in Singapore, which include the following:
If there is any contradiction between this document and any written law, the latter shall
take precedence.
As the licensing authority under the Medicines Act, the Chief Executive of the Health
Sciences Authority (HSA) and the officers in HSAs Health Products Regulation Group
(HPRG) have the authority to grant, renew, vary, suspend and revoke licences and
certificates under the Medicines Act. Applicants are strongly encouraged to familiarise
themselves with the contents of this guidance document before submitting their
applications.
This guidance document describes the procedures and requirements for submitting an
application to obtain a new Product Licence or to make variations to an existing
registered medicinal product.
Applicants are expected to comply with the procedures and requirements laid out in this
guidance. However, alternative approaches to the specified procedures and requirements
may be accepted, provided there is adequate scientific evidence and justification. Any
alternative approach should be discussed with HSA and agreed upon in advance in order
to avoid rejection of the application. Conversely, HSA may request for information or
specify conditions not described in this document that 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 describe
preclinical, pharmacological and toxicological data.
Applicants are advised to check HSAs website1 for the latest version of this guidance
document and other related medicinal product registration guidelines.
1
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
Under the Medicines Act, a medicinal product refers to any substance or article (not SEPTEMBER
being 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.
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 three
forensic classes:
Prescription Only Medicine (POM);
Pharmacy only medicine (P); or
General Sale List medicine (GSL).
The following also needs to be taken into consideration when deciding whether a product
should be classified as a POM:
2
Direct danger: Adverse reactions for which there is no preventive action or which are serious, severe or of
high frequency
3
Indirect danger: Masking of an underlying condition that requires medical attention e.g. cancer, heart
disease
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 to lead to medicinal abuse or addiction if used incorrectly SEPTEMBER
or to be used for illegal purposes;
iii. Whether the product contains a substance which, by reason of its novelty or
properties, has the potential to fall within point (ii) above;
iv. Whether the product, by reason of its pharmaceutical characteristics, is reserved for
treatments which can only be instituted in a hospital;
v. Whether the product is used in the treatment of conditions which must be diagnosed
in 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 characteristics
which 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.
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 applicants
responsibilities start with the registration of the medicinal product and end when the
product 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 responsibility
to inform HSA when these changes occur as per the current guidelines.
i. To ensure that all of the information given in the application form and supporting
documents are true and valid, and that all current data, reports and information
relevant to the benefit/risk assessment of the medicinal product have been supplied
at the time of the application submission;
ii. To ensure that all information and material included in the application dossier on
paper exactly matches the information and material included in the electronic
submission dossier. No information has been added, removed, or changed;
iii. To declare at the time of submission to HSA that the application submitted to HSA
has not been rejected, withdrawn, approved via appeal process or pending deferral
by any drug regulatory agency or HSA reference regulatory agencies, with reasons SEPTEMBER
in 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 and
throughout the products life cycle in the Singapore market;
v. To notify HSA if the application submitted to HSA has been rejected, withdrawn or
deferred by any drug regulatory agency or HSA reference regulatory agencies, with
reasons in each case if applicable, throughout the products life cycle in the
Singapore market;
vi. To respond to HSAs queries or requests for more data for review, within the
timelines 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 all post-approval licensing conditions attached to the product licence
and post-approval commitments are fulfilled within the stipulated timelines;
ix. To notify HSA of any changes to the products quality, efficacy or safety throughout
the products life cycle in the Singapore market;
xi. To ensure that all information provided to HSA is true and correct to the best of
his/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 or
declaration in connection with an application submitted to HSA, he/she shall be
guilty 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 39
requires countries to protect the test data of a pharmaceutical product against disclosure
and unfair commercial use.
Section 19D was introduced in July 2004, in order for Singapore to fulfil its obligations
under Article 16.8.1 of the US-Singapore Free Trade Agreement (FTA), stating that the
licensing authority may not grant marketing approval for a product on the basis of the
grant 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.
4 PATENT LINKAGE
Provisions for linkage between patent and marketing approval were introduced in July SEPTEMBER
2004, under Section 12A of the Medicines Act, in order for Singapore to fulfil its
obligations 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 a
product licence and power for the licensing authority to revoke a product licence in
relation to patent infringement and patent declaration. Relevant parts include sections
12A, 16 and 20 of the Act, and paragraph 5B of the Medicines (Licensing, Standard
Provisions and Fees) Regulations.
All applications for new product licences shall be accompanied by patent declarations
required under Section 12A of the Medicines Act. The applicant is required to furnish the
patent 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 of
application submission, and at any other such time as HSA may require. As a general
guidance, a confirmatory declaration will be requested when an approvable regulatory
decision is issued. The applicant is required to furnish the confirmatory declaration within
the timeframe stipulated by HSA.
All declarations required under Section 12A of the Medicines Act should be submitted in
hard copies on original letterhead, signed by the person authorised to make the
declaration on behalf of the applicant. The authorised person is ordinarily an officer of the
company such as a director, the company secretary as registered with ACRA, or
equivalent. Evidence of such authorisation by the applicant of that person to make the
declaration on its behalf shall be submitted together with the declaration. Examples of
evidence of authorisation include a resolution of board of directors, a resolution of a
general meeting of the company, or an extract of the relevant portion of the companys
articles of association. Declaration forms must bear the original signatures of the
authorised person and the company stamp of the applicant.
Under Section 12A (3) of the Medicines Act, the licensing authority may, if the applicant
has declared that in his opinion and to the best of his belief the patent is invalid or will not
be infringed by the performing of the act for which the licence is sought (i.e. Category B
patent declaration), or if the licensing authority considers it appropriate in any particular
case, require the applicant to serve a notice to the proprietor of the patent in the form
prescribed in Part II of the Sixth Schedule of the Medicines (Licensing, Standard
Provisions 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 not
consented to nor acquiesced in the grant of the product licence, and (iv) the applicant is
requesting for grant of product licence after the expiry of the patent (i.e. Category A3
patent declaration), then such an application may not be made earlier than 18 months
before the expiry of the patent.
Applicants should take note that the information contained in this section is for the
purpose of guiding applicants in their patent declarations. Applicants requiring legal
advice should seek the assistance of their own legal counsel.
PRE-SUBMISSION
PREPARATION
APPLICATION
NON-ACCEPTANCE / SUBMISSION
WITHDRAWAL
APPLICATION
SCREENING
ACCEPTANCE
APPLICATION
EVALUATION
NON-APPROVAL /
WITHDRAWAL
REGULATORY
DECISION
APPROVAL
POST-APPROVAL
CHANGES
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 involves
i. 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.
In applying for a new Product Licence for a medicinal product in Singapore, there are two
categories of applications: a new drug application (NDA) and a generic drug application
(GDA):
4
Note for Guidance on the Investigation of Bioavailability and Bioequivalence. CPMP/EWP/QWP/1401/98.
There are three types of evaluation routes for registration of a new product: SEPTEMBER
Full dossier: Applies to any product that has not been approved by any drug
regulatory agency at the time of submission.
Abridged dossier: Applies to any product that has been evaluated and approved by
at least one drug regulatory agency.
Verification dossier: Applies to any product that has been evaluated and approved by
HSAs 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 the
application 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 the
selection of appropriate evaluation routes for NDA, GDA and biosimilar product
applications, respectively.
NOTE: Refer to Section E for more information on the application types and
evaluation routes available for biosimilar products.
Applicants are to note that all advice given by HSA will be based on knowledge that is
current at the time of the consultation. Such advice is not binding and does not have a
direct bearing on the eventual outcome of the application concerned.
The applicant may submit a pre-submission inquiry via e-mail if any clarification on
medicinal product registration is needed prior to submission. The e-mail address is:
HSA_MedProd_Registration@hsa.gov.sg. 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 will
be sent back to the applicant.
made in writing, with the purpose, agenda and proposed date & time for the meeting, via
email to HSA_MedProd_Registration@hsa.gov.sg.
SEPTEMBER
For a submission under the full evaluation route, the applicant is required to notify HSA
via a pre-submission meeting two months prior to the intended submission date of the
application dossier.
6 APPLICATION SUBMISSION
Application submission comprises of two parts: the PRISM application form and the
registration dossier.
All applications must be made on-line via PRISM. Refer to Chapter J for guidance notes
for submitting a PRISM application.
The registration dossier contains the documents to support the evaluation of the
submitted application.
The complete dossier should be submitted within 2 working days after the PRISM
application submission to prevent delays in processing of the application. The date of
submission will be defined as the date when HSA receives the complete dataset for
the application.
Registration dossiers should be in a CTD format. The CTD provides a common format for
the preparation of a well-structured submission dossier. It uses a modular framework
described in ICH Topic M4 5 or the ASEAN guidelines on the Common Technical
Document for Registration of Pharmaceuticals for Human use: Organisation of the
Dossier6. This guidance document should be read in conjunction with the most recent
version 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 ACTD
format. 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 the
numbering and naming of the sections, as seen in Table 1:
5
http://www.ich.org/
6
http://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 this SEPTEMBER
guidance document will continue to be necessary as a result of experience gained.
The CTD format cannot be changed once the application is submitted. Any subsequent
variation applications for the product should follow the same format.
Applicants should ensure that all soft copies e.g. scanned documents of the dossier
are legible as illegible soft copies will cause unnecessary delays in the registration
process.
Table 2 and 3 outline the softcopy requirements for NDAs and GDAs submitted via the
full, abridged or verification evaluation route in either ICH or ACTD, respectively:
Table 2. Soft and Hard Copy Requirements for ICH CTD dossiers.
#
CTD Requirement
ICH CTD NDA (F) NDA (A) NDA (V) GDA (A + V)
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 PRISM/CD PRISM/CD
Module 3 PRISM/CD PRISM/CD PRISM/CD
PRISM/CD N/A N/A N/A N/A
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)
For Modules 2 to 5/Parts II to IV, applicants can opt to attach the documents either in full
into PRISM section 7 (Supporting Attachments) or submit the softcopies (e.g. PDF
format) in a CD/DVD. However, applicants are advised not to combine PRISM
attachments with a CD/DVD submission i.e. all supporting documents must be attached
in PRISM or all supporting documents submitted in a CD/DVD.
In order to ensure that the dossier is complete, application checklists for both ICH CTD
and ACTD dossiers are provided in Appendix 2A and 3A, respectively. Each checklist
states 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 the
CTD format with folders and subfolders and to include bookmarks to facilitate
screening/reading of the reports.
Applicants must ensure that access to the CD/DVD is not restricted. If so, the applicant
must provide the password(s) to access the CD/DVD contents.
Upon acceptance of the application for evaluation, applicants will be notified if additional
copies of clinical documents (in CD/DVD) will be required.
6.2.2 Language
If the foreign document is an original and bears the seal and signature of a recognised
government agency, the document does not require notarisation. Any other type of
document, such as declarations, translations, photocopies, documents lacking an original
signature, etc., must be notarised by a notary public in the country where the document
was issued before the document can be authenticated. The notary public will sign the
document and affix their seal. Notarisation is generally not required for documents
executed 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;
Applicants are advised to consult the Singapore Embassy/Consulate in the country where
the document originated on local requirements for document legalisation, as these may
deviate from the process as outlined in the preceding paragraph.
Certificates and documents issued in English by drug regulatory agencies do not require
authentication.
Apostille
By international agreement, an apostille can be issued for documents that are to be used
in another country that is party to the Hague convention. When an apostille stamp is
attached to a document, it is exempted from all forms of confirmation i.e. no further
legalisation from a foreign embassy is normally required. Although Singapore at present
is not a party of the Hague Convention, an apostille is acceptable for the authentication of
documents that are submitted to HSA as part of the application dossier.
A certified true copy certifies that the photocopy presented is a true and accurate copy of
the original document. Acceptable certification of documents to support product
applications to HSA can be done by the Company Director or Company Secretary as
registered with ACRA or above, or by an independent authority such as a lawyer, notary
public, Commissioner for Oaths/Declarations/Affidavits, Justice of Peace, the original
issuer of the document or Embassy/Consulate. A notarised copy is the same as a
certified true copy.
A certified true copy of approval letters requires certification by the drug regulatory
agency that issued the approval letter, a notary public or the Singapore
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 available on the drug
regulatory 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 the
correct application type has been chosen and that there are no deficiencies that would
delay the registration process.
If the application type needs to be re-categorized, for example from NDA-2 to NDA-3 or
GDA-1 to NDA-2, the applicant will be notified and subsequently, the PRISM application
will be amended as described in section 11.2.1.
If any deficiencies are identified, a screening query letter via Input Request will be issued
to the applicant. The stop-clock starts whenever HSA requests for clarification or
additional information. The stop-clock ends when HSA receives a complete and SEPTEMBER
satisfactory 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 deficiencies
noted must be addressed before the dossier can be accepted for evaluation.
When the response to the screening query letter has been received, the requested
information and documents will be screened for completeness. The dossier will be
accepted when all requested information, and hence, the registration dossier, is found to
be adequate.
An acceptance notice will be issued to the applicant via email upon acceptance of an
application. The date of acceptance of the application will be considered as the start of
the evaluation timeline.
If the applicant fails to provide the requested information, or the submitted information is
incomplete or contains unsolicited information, the application will not be accepted for
evaluation. A non-acceptance letter will be issued by HSA and the documents will be
returned. If the applicant wishes to resubmit the dossier at a future time, it will be
processed as a new application.
Applicants are advised to ensure that the dossier is compiled according to the required
format. Failure to arrange the submission dossier accordingly will lead to non-acceptance
of the dossier without screening.
NOTE: The screening process only determines the completeness of the registration
dossier for evaluation. Acceptance of the dossier for evaluation does not constitute
acceptability of the data provided. Acceptability of the data can only be determined
during evaluation of the application.
8 APPLICATION EVALUATION
Upon acceptance of an application, evaluation by HSA is based on the data set submitted
by the applicant. A query letter will be issued to the applicant if clarification or additional
information is required.
The stop-clock starts whenever HSA issues a query letter and ends when HSA receives a
complete 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 possible
after 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 be
considered, unless requested by HSA or mutually agreed upon by HSA and the applicant
prior to acceptance.
For applications submitted in PRISM on or after 15 April 2009, applicants can check on
the progress of the evaluation for certain application types and evaluation routes. Table 4
describes the applicable product applications and the stages to the evaluation process: SEPTEMBER
Table 4. Product Applications Applicable for Notification of Stages During Evaluation
Stages of Notification to st nd rd th
1 Stage 2 Stage 3 Stage 4 Stage
Applicant
Evaluation Status
Application Dossier
Type type Accepted for Active Midway in Evaluation
Evaluation Evaluation Evaluation Completed
Application is Evaluation is
approximately completed for the
NDA-1 midway through application
Full or
NDA-2 the evaluation
Abridged Application is (provided that Application is now
NDA-3
accepted for When active there were no undergoing the
evaluation evaluation is in prior stop-clocks regulatory decision
progress for which may affect phase, after which
This marks the the application the evaluation a regulatory
start of the progress) decision letter*
evaluation would be issued.
GDA-1 Abridged or timeline Applicants could
GDA-2 Verification expect to receive Applicants could
the first set of still expect further
queries from HSA queries from HSA
during this stage during this stage
* The issuance of a regulatory decision letter would mark the end of the evaluation timeline for a product
application.
Applicants may view the evaluation stage via track@PRISM. Screenshots on viewing the
change in stages of a pending application are as follows:
SEPTEMBER
Active Evaluation
During the evaluation process, HSA may determine that the application is more suitably
evaluated 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 evaluation
process, when necessary. These experts include scientists and clinicians from both local
and overseas institutions. All external evaluators and experts are bound by agreement to
protect the information made available to them. The identity of the external evaluators is
kept confidential.
9 REGULATORY DECISION
A regulatory decision is made based on the outcome of HSAs evaluation of the submitted
data 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;
Approvable when the application has minor deficiencies;
Non-approvable when the application has major deficiencies; or
Rejection when the response provided by the applicant fails to address the major
deficiencies highlighted in HSAs non-approvable decision.
If an approvable regulatory decision has been reached, the conditions for approval will
be stated in writing and the applicant will be required to fulfill these conditions within the
stipulated timeframe.
If a non-approvable regulatory decision has been reached, the applicant will be informed
of 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 specified
timeframe. 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 will
be considered, unless mutually agreed between HSA and the applicant.
Applicants should note that issuance of a regulatory decision letter signals the end of the
evaluation timeline. Appendix 1 contains information on the application timelines.
An application will be considered withdrawn if the applicant fails to reply within the
stipulated timeframe subsequent to an approvable or a non-approvable decision. Once an
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, an
official letter of commitment is required before the licence can be issued. The letter of
commitment should be specific, i.e. it addresses the particular issues of concern and
should provide details on how and when the post-approval licensing commitments will be
fulfilled. Failure to comply with these commitments may result in the suspension or
revocation of the Product Licence.
Applicants are expected to view the licensing conditions on-line in order to be reminded of
all post-approval commitments associated with the Product Licence.
10 POST-APPROVAL CHANGES
HSA must be notified of any changes to the products quality, efficacy and safety as per
Chapter F in this Guidance.
11 FEES
The fee structure and quanta are subject to on-going review. For updated information on
fees, please visit the HSA website7.
The screening fee per application is payable at the time of PRISM submission. The
screening fees are non-refundable once the application has been successfully submitted
via PRISM.
Applicants are advised to ensure that the dossier is compiled according to the required
format. Failure to arrange the submission dossier accordingly will lead to non-acceptance
of the dossier without screening. In these instances, the screening fees will be forfeited.
Evaluation fees are payable upon acceptance of the dossier for evaluation. The
evaluation fees are non-refundable once the application is accepted, regardless of the
final decision by HSA.
With effect from 15 April 2009, the progressive payment scheme was implemented to
allow payment of evaluation fees by instalments. This is an optional opt-in payment
scheme catered for companies who are under the GIRO payment scheme and only
applicable to applications types as listed in Table 5 on the next page:
7
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/
fees.html
NOTE: To apply for the progressive payment for applications under the full
evaluation route, the applicant must contact HSA via
HSA_Medprod_Registration@hsa.gov.sg to request for a hardcopy progressive
payment application form prior to the submission in PRISM.
For applicants that had chosen the progressive payment scheme, in the event of an
application withdrawal at any point in time during the evaluation stage, any fees that had
been charged, but not yet collected, would still have to be paid; all evaluation fees that
had been paid are non-refundable.
Changes in the evaluation fees may occur if there are changes to the application type.
Re-categorisation of the application within the same application type (e.g. from NDA-2 to
NDA-3, or GDA-1 to GDA-2) would be carried out by the HSA officer during screening
prior to acceptance of the application. As there are differences in evaluation fees for
different application types, the change in application type would be communicated to the
applicant during the screening process. Applicants may opt to withdraw the application if
they do not agree to the change in application type; applicants are to note that in these
instances, 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.
The screening fees for the original application are non-refundable. As such, applicants
are advised to consult HSA on the correct application category when in doubt.
12 APPLICATION TYPES
13 EVALUATION ROUTES
There are three evaluation routes for an NDA: full, abridged and verification evaluation.
The eligibility criteria are different for each evaluation route. Applicants should be familiar
with the criteria for each evaluation route because each route will have different
documentary requirements.
Figure 3 below is a schematic diagram to illustrate the evaluation routes for NDAs:
NO
NDA 1 Is the product FULL ROUTE
registered with NO
any drug ABRIDGED
regulatory ROUTE
NDA 2 agency?
Approved by
NDA 3 HSAs reference
YES
agencies and VERIFICATION
met verification
criteria? YES ROUTE
Full evaluation will apply to a product that has not been approved by any drug regulatory SEPTEMBER
agency at the time of submission.
Abridged evaluation will apply to a product that has been approved by at least one drug
regulatory agency at the time of submission.
For NDAs submitted via the abridged evaluation route, the applicant may request for
priority review for a life-saving drug if there are unmet medical needs. The following
states the criteria that will be considered for priority review:
b) Disease conditions that are of local public health concerns will be given primary
consideration 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 submission and
accompanied by justification which warrants a priority review and how the product is
expected 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 on
a 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;
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 the
point of acceptance of the application for evaluation.
If the NDA is for a non-prescription medicine and is submitted via the abridged evaluation
route, the applicant may submit a written request for a waiver of clinical data submission.
Eligibility for waiver is subject to the criteria defined in Appendix 5 Guideline on
Submission Requirements for Non-Prescription Medicines. However, HSA reserves the
right to request for the complete clinical data set if it is deemed appropriate.
Medicinal products with similar indication(s), dosing regimen(s), patient group(s), and/or SEPTEMBER
direction(s) for use that have been approved by at least two of the following HSAs
reference drug regulatory agencies may be submitted via the verification evaluation route.
HSAs reference drug regulatory agencies are:
However, approval by these reference regulatory agencies does not obligate HSA to
approve 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 primary reference
agency. The chosen primary reference agency is defined as the reference agency for
which the qualifying supporting documents (as outlined in this guidance) will be
submitted.
The proposed indication(s), dosing regimen(s), patient group(s) and/or direction(s) for use
should be the most stringent amongst those approved by the reference regulatory
agencies. In the event that the chosen primary reference agency does not bear the most
stringent indication(s), dosing regimen(s), patient group(s) and/or direction(s) of use, the
clinical assessment report from the other reference agency that met such requirements
should be submitted. The clinical assessment report from the other reference agency to
be submitted may be obtained from the public domain. The proposed PI/PIL should be
identical to that approved by this reference agency (with the exception of country-specific
information).
For a product with a proposed indication that has been designated as an Orphan Drug by
at least one reference agency or a product that has been approved by at least one
reference agency via an accelerated/fast-track approval, approval under exceptional
circumstances or equivalent approval process, the applicant should consult HSA on the
eligibility of such a product through the verification route prior to submission.
For the NDA-3 application type, the verification evaluation route may be applied to the SEPTEMBER
registration of subsequent strengths of a currently-registered product in Singapore. To
qualify for the verification evaluation route for an NDA-3 application, if the product has
been evaluated and approved
by at least one of HSAs reference drug regulatory agencies, then the NDA-3 must
be submitted within two years from the date of approval by that reference agency;
OR,
by at least two of HSAs reference drug regulatory agencies, then the NDA-3 must
be submitted within three years from the date of approval by the chosen primary
reference agency.
All other eligibility criteria for the verification evaluation route as stated above in section
13.1.3 will apply except the following:
The proposed indication(s), dosing regimen(s), patient group(s), and/or direction(s)
for use must be identical to the corresponding approved NDA-1 and/or NDA-2
product(s); and,
The proposed PI/PIL should also be consistent with that currently approved for the
corresponding NDA-1 and/or NDA-2 product(s).
14 DOCUMENTARY REQUIREMENTS
Table 6 outlines the CTD Modules/Parts required for NDAs submitted under each
evaluation route:
Applicants should use Appendix 2A and 3A as a guide to ensure that the dossier is
complete.
The administrative documents relate to Module 1 of the ICH CTD or Part I of the ACTD
and are applicable to all evaluation routes for NDAs. The following sections are to be
submitted:
The comprehensive table of contents is a complete list of all documents provided in the SEPTEMBER
application dossier by Module/Part. The location of each document should be identified
by the Module/Part number. If a hardcopy registration dossier is submitted, then the
location 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).
Applicants should give a concise summary of the application and justify the need for the
application for example, whether the product presents an advantage to patient groups
in terms of improved quality, safety and efficacy compared to available alternatives.
Applicants should also justify the lack of certain documents within the dossier and any
deviation from the guidelines.
Applicants are required to provide the artwork/drafts of the proposed Singapore product
labels, PI and/or PIL for the product. Submission of the proposed PI or PIL is dependent
upon the forensic classification of the product to be registered, as described in the table
below:
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 the
labelling, applicants must provide an official statement to declare that the non-English text
is complete, accurate and unbiased information and is consistent with the English text.
This section refers only to applications submitted under the verification evaluation route.
Assessment reports and supporting documents issued by the primary reference agency
and inserted into this section must be unredacted and unedited. Applicants should refer to
section 14.6.3 for specific details on the required documents.
SEPTEMBER
Description of Batch Numbering System (section 1.7)
For an abridged evaluation of an NDA product, proof of approval by any drug regulatory
agency is required. Proof of approval must come in the form of:
an official approval letter, or equivalent document (e.g. Certificate of Pharmaceutical
Product), which certifies the registration status of the drug product; and
the SPC, PI and/or PIL approved by the drug regulatory agency that issued the
approval letter.
If the SPC is in a non-English language, applicants should refer section 6.2.2 for more
information.
Note that all aspects of the products quality and intended direction(s) for use in
Singapore should be the same as approved by the drug regulatory agency that issued the
approval 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), if
deemed appropriate.
If the brand name (trade name) of the product as registered in the country which issued
the proof of approval is different from that proposed in Singapore, the applicant is
required to submit a declaration letter from the product owner to declare that both
products marketed under the different brand names are identical in all aspects of quality,
safety and efficacy except for the brand name.
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 local
applicant firm to apply for and be the Product Licence Holder for a specific
medicinal 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 for
Singapore. If there are multiple drug product manufacturers, then the applicant may
opt to submit one authorisation letter which clearly states all of the manufacturers
(names and addresses) and their responsibilities related to the drug product. For
biologic drug products, an additional authorisation letter from the Product Owner to
the Drug Substance Manufacturer is required. SEPTEMBER
iii. from Product Owner to Batch Releaser (1.10.3) this letter authorises the specified
company to batch release the drug product. If there are multiple sites responsible
for batch release of the product, then the applicant may opt to submit one
authorisation letter which clearly states all of the batch releasers (names and
addresses) and their responsibilities.
Applicants are to ensure that all names and addresses in the authorisation letters must be
consistent with the information provided in PRISM and the dossier. For Manufacturers
and Batch Releasers, the actual site address of the named company should be stated in
the letter(s) i.e. do not state the office address. Any discrepancy found will delay the
registration process.
All authorisation letters should also state specific product details, including the product
name, dosage form and strength.
Applicants also have the option to combine authorisation letters as stated above into one
document, provided that all names, addresses and responsibilities are clearly stated.
Documentary evidence must be provided to certify that the manufacturer(s) complies with
current applicable GMP standards. Applicants must submit a GMP certificate issued by a
drug regulatory agency for all drug product manufacturing sites including, but not limited
to, bulk product manufacturers, primary packagers and secondary packagers. A CPP
may be submitted in lieu of a GMP certificate provided that the manufacturers name(s)
and address(es) is(are) stated on the CPP. Applicants should note that the names and
addresses 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 of
submission 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 packaged
together 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 to
the drug product e.g. proof of GMP compliance.
For biologic NDA applications, proof of GMP compliance for the drug substance must be
submitted in addition to the aforementioned GMP requirements.
For products manufactured in the USA, if the applicant is unable to obtain any proof of
GMP compliance (in the form of CPP or GMP certificate) from either US FDA or other
drug regulatory agencies, the applicant is required to submit the latest Establishment
Inspection Report (EIR) issued by US FDA and any other relevant supporting document*
for proof of GMP compliance. The applicant is also required to provide the following
information if an EIR does not contain such information:
All new overseas drug product manufacturing sites not previously registered with HSA
before 1st April 2004 and who intend to register their Western medicinal products in
Singapore will be subjected to a GMP Conformity Assessment by HSA. Thus, when
applicable, applicants must also submit a GMP Conformity Assessment application form8
with the required documents as stipulated in the Guidance Notes on GMP Conformity
Assessment of an Overseas Manufacturer9.
HSA reserves the right to request for additional or updated documents as evidence of
GMP compliance during the course of the registration process for example, an updated
GMP certificate in support of the product application or of a GMP Documentary Evidence
Evaluation Application. HSA also reserves the right to conduct an audit of any overseas
manufacturer irrespective of the documentary GMP evidence that is cleared by HSA, if
deemed appropriate.
The Patent Declaration form is required for each NDA. An original, signed and dated
hardcopy patent declaration form should be submitted for each application. Applicants
should refer to section 4 on information on patent linkage and Appendix 7 for a copy of
the Patent Declaration Form.
Here are some points to note when filling the Patent Declaration form:
i. Section 1 Applicant Particulars - state the name and address of the local
company.
ii. Section 2 Product Particulars - state the product name, name and strength of
active ingredient and dosage form. It should be consistent with that stated in
PRISM, all product labelling and all other relevant documents in the dossier.
iii. Section 3 Application Category - declare the patent category that your product
falls under (with respect to a Singapore Patent as registered with IPOS).
iv. Section 4 Information for Category A1 Applications - applicable if category A1 is
selected in Section 3.
v. Section 5 Information for Category A2 Applications - applicable if category A2 is
selected in Section 3. Check the box which is relevant and provide details of the
patent in force.
vi. Section 6 Information for Category A3 Applications - applicable if category A3 is
selected in Section 3. Provide details of the patent in force.
vii. Section 7 Information for Category B Applications - applicable if category B is
selected in Section 3. Check the box which is relevant and provide details of the
patent in force.
viii. Section 8 Declaration - the patent declaration must be signed by the person
authorised to make the declaration on behalf of the company named in Section 1.
8
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/audit_icensing_
manufacturers/conformity_assessment/eServices_Forms.html
9
http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/gmp/files_1.Par.60707.
File.dat/GUIDE-MQA-020-007.pdf
Evidence of authorisation for Section 8 of the form could be in the form of:
An ACRA printout (BizFile) listing the Company Directors/Secretary;
Resolution of board of directors;
Resolution of a general meeting of the company; or,
Extract of the relevant portion of the companys articles of association.
Declaration forms must bear the original signatures of the authorised person and the
company stamp of the Applicant.
The patent declaration form needs to be submitted twice: at the time of dossier
submission and prior to issuance of the Product Licence (upon request by HSA), if the
evaluation was deemed satisfactory with respect to the products safety, efficacy and
quality aspects.
NOTE: the applicant should ensure that the information provided in the patent
declaration form and the evidence of authorisation is current at the point of
submission.
The document required for this section is a declaration letter that states that the
application as submitted to HSA or similar direction of use including indication(s), dosing
regimen(s) and patient population(s)
has not been rejected or withdrawn,
has not been approved via an appeal process, or,
is not pending deferral
by any drug regulatory agency. If any of the conditions apply to the application, details
and reasons must be provided to HSA.
A declaration must be provided to state that all aspects of the products quality are
identical to that currently approved by the chosen primary reference regulatory agency.
Quality aspects include, but are not limited to, formulation, manufacture site(s), release
and shelf life specifications and primary packaging.
If a Drug Master File is submitted, then a second declaration must also be provided to
state that the DMF submitted to HSA is identical to that submitted to the primary
reference regulatory agency.
The registration status of the product in other countries should be entered into PRISM
section 4.9 refer to section 25.1.4.9 of this document for further details.
In the event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered. The full details should
then be attached in softcopy (PDF) in PRISM section 7 (Supporting Attachments) and
submitted in hardcopy in this section of the CTD dossier. The document should be in the
format as seen in Table 7 below:
SEPTEMBER
Table 7. Table of Information on Registration Status in Other Countries for CTD section 1.15.
Country Application Status Date Approved application Approved
status indication/dosing regimen details* forensic
classification
Country 1 Approved 12 Jan 2005 Adjuvant treatment of colorectal cancer POM
stage III (Dukes C) following complete
resection of primary tumour.
Country 2 Approved 2 Feb 2006 Adjuvant treatment of colorectal cancer POM
following surgery
Country 3 Withdrawn 14 Apr 2002 Indication submitted Adjuvant POM
by applicant treatment of colorectal cancer.
Withdrawn due to insufficient long-term
efficacy data (only phase II data
submitted).
Re-submitted on 16 June 2005 with
completed phase III data for Adjuvant
treatment of colorectal cancer following
surgery.
Country 4 Approved 21 Nov 2004 Adjuvant treatment of colorectal cancer POM
stage III (Dukes C) following complete
removal of primary tumour.
The overview and summary documents are to be inserted into Module 2 of the ICH CTD
or into the relevant sections in Part II, III and IV of the ACTD.
A completed Singapore Quality Overall Summary (SQOS) must also be inserted into
Module 2, section 2.3 of the ICH CTD or Part II, section B of the ACTD, irrespective of
whether an ICH or ACTD QOS has been included in the application dossier. Take note
that the SQOS must be named and dated by the applicant prior to submission. The
electronic copy of the Singapore QOS should be in Microsoft Word format.
NOTE: the SQOS is only a summary of the technical information in the dossier.
Pages from the SQOS should not be used to replace documents required for the
application.
Here are some points to note when filling out and submitting the SQOS with the
application:
i. The information in the SQOS should be based on the documents located in each of
the CTD dossier sections provided by the drug product manufacturer;
ii. All of the tables in all of the SQOS sections should be filled out if there is missing
information, an Input Request will be sent to request to complete the SQOS; and,
iii. During screening of the application, all of the information in the relevant SQOS SEPTEMBER
sections should be updated when additional or updated documents are submitted in
response to an Input Request.
The SQOS template for chemical drug products is given in Appendix 8. The SQOS
template for biologic drug products, including biosimilar products, is given in Appendix 9.
The quality documents relate to Module 3 of the ICH CTD or Part II of the ACTD. In
addition to the ICH or ACTD technical content requirements, the following explanatory
notes pertain to requirements specific to Singapore:
The ICH M4Q technical guideline and ASEAN Common Technical Requirements (ACTR)
provide details on the information to be included in the drug substance sections of an
application dossier.
NOTE: if a drug product contains more than one drug substance, the information
within Module 3.2.S (ICH CTD) or Part II.S (ACTD) must be provided in its
entirety for each drug substance.
All of the drug substance sections of the CTD i.e. S1 to S7 should be submitted in the
application. If these sections are incomplete, then the dossier should make reference to a
Drug Master File (DMF), Plasma Master File (PMF) or Certificate of Suitability of
Monographs of the European Pharmacopoeia (CEP).
Because the drug product manufacturer is responsible for quality control of the drug
substance that is used in the drug product, applicants should note that the complete S
section of the CTD dossier should be provided by the drug product manufacturer
regardless of whether a DMF or CEP has been submitted in support of a product
application.
A Drug Master File is a reference that provides information about specific processes or
components used in the manufacturing, processing, and packaging of a drug. The DMF
contains information of a proprietary nature that is not available to the drug product
manufacturer or to the applicant of a product registration submission.
If a drug substance is sourced from a manufacturer that is different from the drug product
manufacturer, data on the manufacture, quality control and stability of the drug substance
may be submitted in the form of a DMF. If the drug substance and drug product are
manufactured by the same manufacturer, then either a DMF or complete S section can
be submitted.
The DMF is divided into two parts: an open (or applicants) part and a closed (or
restricted) part. The open part contains most of the information in Module 3.2.S (ICH
CTD) or Part II.C.S (ACTD) i.e. S1, S2.1 and S3 to S7 sections. The closed part
contains the confidential information in section 3.2.S.2.
The Letter of Access authorises HSA to refer to the DMF in support of the application for
a drug product. Thus, the Letter of Access must state the following:
the name of the drug product(s) (product name, dosage form and product strength)
to be registered;
the local applicant (name and address) responsible for product registration; and,
a declaration that the local applicant and HSA will be notified of any change in the
drug substance specification or in the manufacturing process that will likely affect
the products quality or safety.
If the Letter of Access does not fulfill these requirements, HSA reserves the right to return
the DMF to the DMF holder.
The DMF holder may submit the DMF directly to HSA to maintain confidentiality of the
contents. The information contained in the closed part of the DMF will be regarded as
confidential and will only be evaluated in support of the application(s) mentioned in the
Letter of Access. The confidential information will not be disclosed to any third party
without a written authorisation from the Drug Master File holder.
Upon receipt of the DMF, HSA will assign a DMF number. For future correspondence, the
applicant and the DMF holder should make a reference to the assigned DMF number. If
there are deficiencies within the closed part of the DMF, HSA will raise queries directly
with the DMF holder.
NOTE: Assignment of a DMF number does not constitute approval of the DMF it
is not approved or rejected. It is a separate document that is submitted in support
of an application. A DMF must always be linked to a product application.
Applicants are responsible to maintain and update the DMF. If there are changes to the
DMF that will result in a post-approval variation to the drug product, applicants must file a
post-approval variation refer to Section F of this guidance for more information on the
post-approval process.
alone document or as part of the registration dossier. Appendix 10 describes the PMF
data requirements for submission.
SEPTEMBER
If the PMF is a stand-alone document, then it should be filed separately from the
application dossier for pre-marketing evaluation. The applicant may cross-reference a
currently registered PMF of HSA where applicable.
If reference is made to a CEP, the applicant should submit a copy of the duly authorised,
valid CEP, including all annexes. A duly authorised CEP should contain the following
information in the Declaration of Access section of the CEP:
name of the Product Owner or local applicant;
name of the product to be registered it is recommended that the dosage form and
strength(s) also be stated;
signature and company stamp of the CEP holder; and,
date of authorisation.
The following additional documents must accompany the CEP and inserted into the
relevant CTD S sections:
i. batch analysis results (S4.4) from the drug substance manufacturer demonstrating
compliance with the Ph. Eur. monograph, including any additional tests/limits listed
on the CEP; and,
ii. if applicable, additional data to address any relevant parameter(s) not addressed in
the CEP, such as physico-chemical characteristics (e.g. particle size,
polymorphism, etc) and, if a re-test period is not stated on the CEP, container
closure system (S6) and stability data (S7).
NOTE: HSA reserves the right to request for any additional information about the
CEP-certified drug substance if it is seemed appropriate.
If there is a CEP for animal-derived material used in the drug product, the applicant may
submit the CEP in lieu of the documents stipulated in Appendix 11 Guideline on the
Registration of Human Medicinal Products Containing Materials of Animal Origin.
It is the applicants responsibility to submit the latest CEP updates, with annexes, as soon
as it is available from EDQM.
Batch analysis data should be provided by the drug substance and drug product
manufacturers on the same drug substance batches, if available. While it is not required
to submit data on three batches for CTD section S4.4, the data should be for a
production-sized drug substance batch, if available.
At the time of submission, the minimum stability data required are as follows:
At least 12 months of real time data and 6 months of accelerated data on at least
three primary batches of the drug substance;
The batches should be at least pilot scale-sized and manufactured by a method SEPTEMBER
that simulates the final commercial process.
If the drug substance is sourced from multiple sites, stability data from each site should
be provided.
HSA may request for additional stability data if deemed necessary for the evaluation of
the application.
The ICH M4Q and ACTR also provide details on the information to be included in the
drug product sections of an application dossier.
Detailed descriptions and discussions, with relevant data, which relates to the
development, and hence quality, of the drug product should be provided in the relevant
dossier sections. Examples include, but are not limited to:
polymorphism, solubility or particle size of the drug substance and its effect on the
products quality;
a description and the results of the formulation development;
the rationale for the choice of dissolution method and a discussion of its
discriminatory nature, with data;
compatibility of the container closure system for the product or preservative efficacy
test results; and,
optimisation of the manufacturing process, with data.
The description, documentation and complete results of the validation studies on the
manufacturing process should be provided in the dossier. Particular care should be taken
to ensure that the documents include critical processes for the manufacturing process: for
example, blend uniformity validation for oral dosage forms and terminal sterilisation or
aseptic filling for sterile products.
Where ranges of batch sizes are proposed, it should be demonstrated that variations in
batch size would not adversely alter the characteristics of the finished product.
This section refers to all excipients used in the drug product formulation, including
ingredients used in capsule shells and film coatings. The specifications and analytical
method(s) for each excipient should be described, with validation of any in-house test
method(s) if applicable.
10
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
For excipients derived from human plasma, applicants should refer to the Appendix 10 for
more information on the data requirements.
For excipients derived from animal sources, applicants should refer to Appendix 11,
which is the guideline on the registration of human medicinal products containing
materials of animal origin. The checklist in Annex 1 in Appendix 11 may serve as a guide
to the documentary requirements for submission. Applicants should note that the
completed checklist in Annex 1 is to be submitted in CTD section 3.2.P.4.5 with the
supporting documents submitted in ICH CTD section 3.2.A.2 or ACTD section Q.A.2.
But for milk and certain milk derivatives, such as lactose, because these excipients are
generally considered non-infectious, a declaration from the supplier of the excipient
stating that the milk is from healthy cows fit for human consumption and no other
potentially infectious ruminant-derived materials were used in the manufacturing process
would be sufficient. This declaration is to be submitted in CTD section 3.2.P.4.5.
The drug products release and shelf-life specifications should be declared in section
P.5.1.
Descriptions of all test methods with complete validation results of all in-house methods
should be submitted in sections P.5.2 and P.5.3.
Descriptions (including size, origin and use) and test results of all relevant batches (e.g.
pre-clinical, clinical, pilot and production batches) used to establish the specification and
evaluate the consistency in manufacturing should be provided.
Batch analysis data and/or CoAs on three batches of the drug product should be
provided in section P.5.4.
Technical information about each component of the container closure system(s) used for
the drug product should be included in the dossier. The technical information to be
included in the dossier includes, but is not limited to, schematic diagrams, descriptions,
specifications, analytical methods, CoAs and declarations of compliance to international
standards.
HSA has adopted the ASEAN Guideline on Stability of Drug Product11 for guidance on the
conduct of stability studies for the ASEAN region. Applicants should familiarise
themselves with this guideline prior to submission. Applicants are also reminded that the
ASEAN stability requirements have been implemented since 1st January 2009.
11
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
At the time of submission, the minimum stability data required are as follows:
At least 12 months of real time data and 6 months of accelerated data on primary
batches of the drug product, as per the ASEAN guideline; SEPTEMBER
The primary batches should be manufactured by the same method(s) and
packaged in the same container closure system as that proposed for Singapore.
All submitted stability data must be site specific to the product proposed for Singapore.
For example, if the drug substance is sourced from two different sites (e.g. site A and B),
stability data for the drug product must include one set of minimum requirements for the
drug product with drug substance from site A and one set for the drug product with drug
substance from site B i.e. a total of six batches at real time conditions and 6 batches at
accelerated conditions.
For new product licence applications, one set of Blank Production Batch Records from
the intended site of manufacture may be requested.
The non-clinical documents relate to Module 4 of the ICH CTD or Part III of the ACTD.
Applicants should refer to the ICH CTD Guidelines M4S12 (Safety) technical guidelines or
the ACTD Part III: Nonclinical13 guidelines for detailed information on the contents of non-
clinical documents for the application dossier.
The clinical documents relate to Module 5 of the ICH CTD or Part IV of the ACTD.
Guidance on how to complete this Module/Part is provided in the ICH CTD Guideline
M4E 14 (Efficacy) technical guidelines, in particular the ICH E3 guidance document on
Structure and Contents of Clinical Study Reports, or the ACTD Part IV: Clinical 15
guidelines.
Clinical studies should generally be conducted using the drug product formulation
submitted in the application and in the appropriate patient population for the indication(s)
and/or dosing regimen(s) as requested in the NDA. Biopharmaceutic study reports are
required if the commercial formulation for the Singapore market differ from the clinical trial
formulation used in the pivotal studies.
Risk management plans (RMP) submitted to EMA, risk evaluation and mitigation
strategies (REMS) submitted to US FDA, and/or other relevant documents pertaining to
such purposes should be included, where available. The need to implement a risk
management plan in Singapore would be assessed on a case-by-case basis during the
review process.
12
http://www.ich.org/cache/compo/276-254-1.html
13
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
14
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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 as that approved by the drug
regulatory agency that issued the proof of approval.
The complete assessment report and other relevant supporting documents from the
chosen primary reference agency must be submitted, as tabulated below. The
assessment reports from the primary reference agency must be unredacted or unedited.
Reports from the primary reference agency that are obtained from the public domain are
deemed unacceptable.
Administrative documents specific to the verification evaluation route that are required at
the time of submission include:
i. 1.9 Official approval letters, or equivalent documents, from the relevant reference
regulatory agencies that certify the registration status of the drug product;
ii. 1.13 Official letter declaring that the application submitted to HSA or similar
direction(s) of use, indication(s), dosing regimen(s) and/or patient group(s) have not
been rejected, withdrawn, approved via appeal process16, or pending deferral17 by
any drug regulatory agency, with reasons in each case if applicable;
iii. 1.14 Official letter declaring that the Drug Master File provided is the same as that
submitted to the primary reference agency, if applicable; and,
iv. 1.14 Official letter declaring that all aspects of the products quality intended for
sale in Singapore are identical as that 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 and primary packaging.
16
Approval via appeal process includes, but is not limited to, the following: approval following negative
opinion, approval following rejection, approval following non-approvable etc.
17
Deferral includes, but is not limited to, the following: non-approvable, approvable, conditional approval,
conditional marketing authorisation, notice of compliance with conditions etc.
All of the data submitted to HSA must be the same as the data package submitted to the
reference regulatory agencies. Differences between the dossier submitted to HSA and
data reviewed by the reference regulatory agencies will not only delay the processing of
the application, but may also lead to re-routing of the dossier to the abridged evaluation
route if significant undisclosed differences have been discovered.
In the event that the chosen primary reference agency does not bear the most stringent
indication(s), dosing regimen(s), patient group(s) and/or direction(s) of use amongst those
approved by the reference regulatory agencies, a supplemental clinical assessment
report from the reference agency that approved the most stringent indication(s), dosing
regimen(s), patient group(s) and/or direction(s) of use is required. Reports from the public
domain are acceptable. The proposed PI/PIL should be identical to that approved by this
reference agency (with the exception of country-specific information).
15 APPLICATION TYPES
The Singapore reference product must be a currently registered product that has been
granted market authorisation based on the evaluation of the products quality, efficacy
and safety i.e. a dossier with chemical, pharmaceutical, pharmacological-toxicological
and clinical data. If such a reference product is not registered in Singapore, then an
alternate registered comparator product may be used if adequately justified by the
applicant and agreed upon by HSA.
The generic product should contain the same active substance(s) and strength(s) and be
the same pharmaceutical dosage form as the Singapore reference product.
For generic products containing a different salt or ester form of the active substance
compared 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 reference
product.
Applicants are advised to search HSAs online database 18 to identify the Singapore
reference product. Applicants submitting GDAs should also refer to Appendix 12 for
further details on product interchangeability and biowaiver request. SEPTEMBER
Applicants are encouraged to contact HSA to discuss the acceptability of a GDA if the
generic product does not have a registered Singapore reference product of the same
strength. In these instances, applicants shall provide scientific justification for HSAs
consideration. However, a generic drug application for a higher strength than the
Singapore reference product will not be accepted.
16 EVALUATION ROUTES
There are two evaluation routes for a GDA: abridged and verification evaluation. The
eligibility criteria are different for each evaluation route. Applicants should be familiar with
the criteria for each evaluation route because each route will have different documentary
requirements.
Figure 4 below is a schematic diagram to illustrate the evaluation routes for GDAs:
NO
Approved by at least ABRIDGED
GDA 1 ROUTE
one of HSAs
reference agencies
and met verification
GDA 2 criteria? VERIFICATION
YES ROUTE
Abridged evaluation will apply to a product that has been approved by at least one drug
regulatory agency at the time of submission.
The verification evaluation route applies to a medicinal product that has been evaluated
and approved by at least one of the following HSAs reference drug regulatory agencies:
However, approval by these reference regulatory agencies does not obligate HSA to
approve the application.
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The chosen reference agency is defined as the reference agency for which the qualifying
supporting documents (as outlined in this guidance) will be submitted.
17 DOCUMENTARY REQUIREMENTS
Table 8 outlines the CTD Modules/Parts required for GDAs submitted under each
evaluation route:
Applicants should use Appendix 2A and 3A as a guide to ensure that the dossier is
complete.
The administrative documents relate to Module 1 of the ICH CTD or Part I of the ACTD
and are applicable to the evaluation routes for GDAs. The following sections are to be
submitted:
The comprehensive table of contents is a complete list of all documents provided in the
application dossier by Module/Part. If a hardcopy registration dossier is submitted, then
the location 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).
Applicants should give a concise summary of the application and justify the need for the SEPTEMBER
application for example, whether the product presents an advantage to patient groups
in terms of improved quality, safety and efficacy compared to available alternatives.
Applicants should also justify the lack of certain documents within the dossier and any
deviation from the guidelines.
Applicants are required to provide the artwork/drafts of the proposed Singapore product
labels, PI and/or PIL for the product. Submission of the proposed PI or PIL is dependent
upon the forensic classification of the product to be registered, as described in the table
below:
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 the
labelling, applicants must provide an official statement to declare that the non-English text
is complete, accurate and unbiased information and is consistent with the English text.
Appendix 6 of this guidance contains specific details on product labelling requirements for
Singapore.
The clinical information in the proposed PI/PIL should be consistent with that currently
approved for the Singapore reference product.
In this section, the applicant shall submit the approved SPC, PI and/or PIL from the drug
regulatory agency that issued the proof of approval.
This section refers only to applications submitted under the verification evaluation route.
Assessment reports and supporting documents issued by the chosen reference agency
and inserted into this section must be unredacted and unedited. Applicants should refer to
section 17.5.2 for specific details on the required documents.
applicable, examples of the batch numbering system should be included to illustrate how
the batch number enables identification.
SEPTEMBER
Proof of Approval (section 1.8, 1.9)
Proof of approval is not required for GDAs undergoing abridged evaluation for finished
products manufactured (up to primary packaging) in Singapore.
For an abridged evaluation of an imported GDA product, proof of approval by any drug
regulatory agency is required. Proof of approval must come in the form of:
an official approval letter, or equivalent document (e.g. Certificate of Pharmaceutical
Product), which certifies the registration status of the drug product; and
the SPC, PI and/or PIL approved by the drug regulatory agency that issued the
approval letter.
If the SPC is in a non-English language, applicants should refer section 6.2.2 of this
guidance document for more information.
Note that all aspects of the products quality, should be the same as approved by the drug
regulatory agency that issued the approval 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), if
deemed appropriate.
If the brand name (trade name) of the product as registered in the country which issued
the proof of approval is different from that proposed in Singapore, the applicant is
required to submit a declaration letter from the product owner to declare that both
products marketed under the different brand names are identical in all aspects of quality,
safety and efficacy except for the brand name.
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 local
applicant firm to apply for and be the Product Licence Holder for a specific
medicinal 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 for
Singapore. If there are multiple drug product manufacturers, then the applicant may
opt to submit one authorisation letter which clearly states all of the manufacturers
(names and addresses) and their responsibilities related to the drug product.
iii. from Product Owner to Batch Releaser (1.10.3) this letter authorises the specified
company to batch release the drug product. If there are multiple sites responsible
for batch release of the product, then the applicant may opt to submit one
authorisation letter which clearly states all of the batch releasers (names and
addresses) and their responsibilities.
Applicants are to ensure that all names and addresses in the authorisation letter(s) must
be consistent with the information provided in PRISM and the dossier. For Manufacturers SEPTEMBER
and Batch Releasers, the actual site address of the named company should be stated in
the letter(s) i.e. do not state the office address. Any discrepancy found will delay the
registration process.
All authorisation letters should also state specific product details, including the product
name, dosage form and strength.
Applicants also have the option to combine authorisation letters as stated above into one
document, provided that all names, addresses and responsibilities are clearly stated.
Documentary evidence must be provided to certify that the manufacturer(s) complies with
current applicable GMP standards. Applicants must submit a GMP certificate issued by a
drug regulatory agency for all drug product manufacturing sites including, but not limited
to, bulk product manufacturer(s), primary packer(s) and secondary packer(s). A CPP may
be submitted in lieu of a GMP certificate provided that the manufacturers name(s) and
address(es) is(are) stated on the CPP. Applicants should note that the names and
addresses 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 of
submission 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 packaged
together 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 to
the drug product e.g. proof of GMP compliance.
For products manufactured in the USA, if the applicant is unable to obtain any proof of
GMP compliance (in the form of CPP or GMP certificate) from either US FDA or other
drug regulatory agencies, the applicant is required to submit the latest Establishment
Inspection Report (EIR) issued by US FDA and any other relevant supporting document*
for proof of GMP compliance. The applicant is also required to provide the following
information if an EIR does not contain:
All new overseas drug product manufacturing sites not previously registered with HSA
before 1st April 2004, and who intend to register their Western medicinal products in
Singapore will be subjected to a GMP Conformity Assessment by HSA. Thus, when SEPTEMBER
applicable, applicants must also submit a GMP Conformity Assessment application form 19
with the required documents as stipulated in the Guidance Notes on GMP Conformity
Assessment of an Overseas Manufacturer20.
HSA reserves the right to request for additional or updated documents as evidence of
GMP compliance during the course of the registration process for example, an updated
GMP certificate in support of the product application or of a GMP Documentary Evidence
Evaluation Application. HSA also reserves the right to conduct an audit of any overseas
manufacturer irrespective of the documentary GMP evidence that is cleared by HSA, if
deemed appropriate.
The Patent Declaration form is required for each GDA. An original, signed and dated
hardcopy patent declaration form should be submitted for each application. Applicants
should refer to section 4 on information on Patent Linkage and Appendix 7 for a copy of
the Patent Declaration Form.
Here are some points to note when filling the Patent Declaration form:
i. Section 1 Applicant Particulars - state the name and address of the local
company.
ii. Section 2 Product Particulars - state the product name, name and strength of
active ingredient and dosage form. It should be consistent with that stated in
PRISM, all product labelling and all other relevant documents in the dossier.
iii. Section 3 Application Category - declare the patent category that your product
falls under (with respect to a Singapore Patent as registered with IPOS).
iv. Section 4 Information for Category A1 Applications - applicable if category A1 is
selected in Section 3.
v. Section 5 Information for Category A2 Applications - applicable if category A2 is
selected in Section 3. Check the box which is relevant and provide details of the
patent in force.
vi. Section 6 Information for Category A3 Applications - applicable if category A3 is
selected in Section 3. Provide details of the patent in force.
vii. Section 7 Information for Category B Applications - applicable if category B is
selected in Section 3. Check the box which is relevant and provide details of the
patent in force.
viii. Section 8 Declaration - the patent declaration must be signed by the person
authorised to make the declaration on behalf of the company named in Section 1.
The authorised person is ordinarily an officer of the company such as Company
Director or Company Secretary as registered with ACRA, or equivalent. Evidence of
such authorisation is to be submitted together with the declaration.
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manufacturers/conformity_assessment/eServices_Forms.html
20
http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/gmp/files_1.Par.60707.
File.dat/GUIDE-MQA-020-007.pdf
Declaration forms must bear the original signatures of the authorised person and the
company stamp of the Applicant.
SEPTEMBER
The patent declaration form needs to be submitted twice: at the time of dossier
submission and prior to issuance of the Product Licence (upon request by HSA), if the
evaluation was deemed satisfactory with respect to the products safety, efficacy and
quality aspects.
NOTE: the applicant should ensure that the information provided in the patent
declaration form and the evidence of authorization is current at the point of
submission.
The document required for this section is a declaration letter that states that the
application as submitted to HSA or similar direction of use including indication(s), dosing
regimen(s) and patient population(s)
has not been rejected,
has not been withdrawn,
has not been approved via an appeal process, or,
is not pending deferral
by any drug regulatory agency. If any of the conditions apply to the application, details
and reasons must be provided to HSA.
A declaration must be provided to state that all aspects of the products quality are
identical to that currently approved by the chosen reference regulatory agency. Quality
aspects include, but are not limited to, formulation, manufacture site(s), release and shelf
life specifications and primary packaging.
If a Drug Master File is submitted, then a second declaration must also be provided to
state that the DMF submitted to HSA is identical to that submitted to the primary
reference regulatory agency.
The registration status of the product in other countries should be entered into PRISM
section 4.9 refer to section 25.1.4.9 of this document for further details.
In the event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered. The full details should
then be attached in softcopy (PDF) in PRISM section 7 (Supporting Attachments) and
submitted in hardcopy in section 1.15 of the CTD dossier. The document should be in the
format as seen in Table 7 on page 35 of this guidance document.
The overview and summary documents are to be inserted into Module 2 of the ICH CTD
or into the relevant sections in Part II, III and IV of the ACTD.
A completed Singapore Quality Overall Summary (SQOS) must also be inserted into
Module 2, section 2.3 of the ICH CTD or Part II, section B of the ACTD, irrespective of
whether an ICH or ACTD QOS has been included in the application dossier. Take note SEPTEMBER
that the SQOS must be named and dated by the applicant prior to submission. The
electronic copy of the Singapore QOS should be in Microsoft Word format.
NOTE: the SQOS is only a summary of the technical information in the dossier.
Pages from the SQOS should not be used to replace documents required for the
application.
Here are some points to note when filling out and submitting the SQOS with the
application:
i. The information in the SQOS should be based on the documents located in each of
the CTD dossier sections provided by the drug product manufacturer;
ii. All of the tables in all of the SQOS sections should be filled out if there is missing
information, an Input Request will be sent to request to complete the SQOS; and,
iii. During screening of the application, all of the information in the relevant SQOS
sections should be updated when additional or updated documents are submitted in
response to an Input Request.
The quality documents relate to Module 3 of the ICH CTD or Part II of the ACTD. In
addition to the ICH or ACTD technical content requirements, the following explanatory
notes pertain to requirements specific to Singapore:
The ICH M4Q technical guideline and ASEAN Common Technical Requirements (ACTR)
provide details on the information to be included in the drug substance sections of an
application dossier.
NOTE: if a drug product contains more than one drug substance, the information
within Module 3.2.S (ICH CTD) or Part 2.S (ACTD) must be provided in its entirety
for each drug substance.
All of the drug substance sections of the CTD i.e. S1 to S7 should be submitted in the
application. If these sections are incomplete, then the dossier should make reference to a
Drug Master File (DMF) or Certificate of Suitability of Monographs of the European
Pharmacopoeia (CEP).
Because the drug product manufacturer is responsible for quality control of the drug
substance that is used in the drug product, applicants should note that the complete S
section of the CTD dossier should be provided by the drug product manufacturer
regardless of whether a DMF or CEP has been submitted in support of a product
application.
A Drug Master File is a reference that provides information about specific processes or SEPTEMBER
components used in the manufacturing, processing, and packaging of a drug. The DMF
contains information of a proprietary nature that is not available to the drug product
manufacturer or to the applicant of a product registration submission.
If a drug substance is sourced from a manufacturer that is different from the drug product
manufacturer, data on the manufacture, quality control and stability of the drug substance
may be submitted in the form of a DMF. If the drug substance and drug product are
manufactured by the same manufacturer, then either a DMF or complete S section can
be submitted.
The DMF is divided into two parts: an open (or applicants) part and a closed (or
restricted) part. The open part contains most of the information in Module 3.2S (ICH CTD)
or Part II.C.S (ACTD) i.e. S1, S2.1 and S3 to S7 sections. The closed part contains the
confidential information in section 3.2.S.2.
The Letter of Access authorises HSA to refer to the DMF in support of the application for
a drug product. Thus, the Letter of Access must state the following:
the name of the drug product (product name, dosage form and product strength) to
be registered;
the local applicant responsible for product registration; and,
a declaration that the local applicant and HSA will be notified of any change in the
drug substance specification or in the manufacturing process that will likely affect
the products quality or safety.
If the Letter of Access does not fulfill these requirements, HSA reserves the right to return
the DMF to the DMF holder.
The DMF holder may submit the DMF directly to HSA to maintain confidentiality of the
contents. The information contained in the closed part of the DMF will be regarded as
confidential and will only be evaluated in support of the application(s) mentioned in the
Letter of Access. The confidential information will not be disclosed to any third party
without a written authorisation from the Drug Master File holder.
Upon receipt of the DMF, HSA will assign a DMF number. For future correspondence, the
applicant and the DMF holder should make a reference to the assigned DMF number.
Should there be deficiencies within the closed part of the DMF, HSA will raise queries
directly with the DMF holder.
NOTE: assignment of a DMF number does not constitute approval of the DMF it
is not approved or rejected. It is a separate document that is submitted in support
of an application. A DMF must always be linked to a product application.
Applicants are responsible to maintain and update the DMF. If there are changes to the
DMF that will result in a post-approval variation to the drug product, applicants must file a
post-approval variation refer to Section F of this guidance for more information on filing
variations.
Certificates of Suitability
If reference is made to a CEP, the applicant should submit a copy of the duly authorised,
valid CEP, including all annexes. A duly authorised CEP should contain the following
information in the Declaration of Access section of the CEP:
name of the Product Owner or local applicant;
name of the product to be registered it is recommended that the dosage form and
strength(s) also be stated;
signature and company stamp of the CEP holder; and,
date of authorisation.
The following additional documents must accompany the CEP and inserted into the
relevant CTD S section:
i. batch analysis results (S4.4) from the drug substance manufacturer demonstrating
compliance with the Ph. Eur. monograph, including any additional tests/limits listed
on the CEP; and,
ii. if applicable, additional data to address any relevant parameter(s) not addressed in
the CEP, such as physico-chemical characteristics (e.g. particle size,
polymorphism, etc) and, if a re-test period is not stated on the CEP, container
closure system (S6) and stability data (S7).
NOTE: HSA reserves the right to request for any additional information about the
CEP-certified drug substance if it is deemed appropriate.
If there is a CEP for animal-derived material used in the drug product, the applicant may
submit the CEP in lieu of the documents stipulated in Appendix 11 Guideline on the
Registration of Human Medicinal Products Containing Materials of Animal Origin.
It is the applicants responsibility to submit the latest CEP updates, with annexes, as soon
as it is available from EDQM.
Batch analysis data should be provided by the drug substance and drug product
manufacturers on the same drug substance batches, if available. While it is not required
to submit data on three batches for CTD section S4.4, the data should be for a
production-sized drug substance batch, if available.
At the time of submission, the minimum stability data required are as follows: SEPTEMBER
At least 12 months of real time data and 6 months of accelerated data on at least
three primary batches of the drug substance;
The batches should be at least pilot scale-sized and manufactured by a method
that simulates the final commercial process.
If the drug substance is sourced from multiple sites, stability data from each site should
be provided.
HSA may request for additional stability data if deemed necessary for the evaluation of
the application.
The ICH M4Q and ACTR also provide details on the information to be included in the
drug product sections of an application dossier.
Detailed descriptions and discussions, with relevant data, which relates to the
development, and hence quality, of the drug product should be provided in the relevant
dossier section. Examples include, but are not limited to:
polymorphism, solubility or particle size of the drug substance and its effect on the
products quality;
a description and the results of the formulation development;
the rationale for the choice of dissolution method and a discussion of its
discriminatory nature, with data;
compatibility of the container closure system for the product or preservative efficacy
test results; and,
optimization of the manufacturing process, with data.
The description, documentation and complete results of the validation studies on the
manufacturing process should be provided in the dossier. Particular care should be taken
to ensure that the documents include critical processes for the manufacturing process: for
example, blend uniformity validation for oral dosage forms and terminal sterilisation or
aseptic filling for sterile products.
Where ranges of batch sizes are proposed, it should be demonstrated that variations in
batch size would not adversely alter the characteristics of the finished product.
This section refers to all excipients used in the drug product formulation, including
ingredients used in capsule shells and film coatings. The specifications and analytical
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method(s) for each excipient should be described, with validation of any in-house test
method(s) if applicable.
SEPTEMBER
Information on proprietary ingredients such as flavourings, colourants, perfumes and/or
printing inks should be as detailed as possible. Applicants are advised not to use internal
codes but rather give commercial names for such ingredients.
For excipients derived from animal sources, applicants should refer to Appendix 11,
which is the guideline on the registration of human medicinal products containing
materials of animal origin. The checklist in Annex 1 in Appendix 11 may serve as a guide
to the documentary requirements for submission. Applicants should note that the
completed checklist in Annex 1 is to be submitted in CTD section 3.2.P.4.5 with the
supporting documents submitted in ICH CTD section 3.2.A.2 or ACTD section Q.A.2.
But for milk and certain milk derivatives, such as lactose, because these excipients are
generally considered non-infectious, a declaration from the supplier of the excipient
stating that the milk is from healthy cows fit for human consumption and no other
potentially infectious ruminant-derived materials were used in the manufacturing process
would be sufficient. This declaration is to be submitted in CTD section 3.2.P.4.5.
The drug products release and shelf-life specifications should be declared in section
P.5.1.
Descriptions of all test methods with complete validation results of all in-house methods
should be included in sections P.5.2 and P.5.3.
Batch analysis data and/or CoAs on three batches of the drug product should be
provided in section P.5.4.
Technical information about each component of the container closure system(s) used for
the drug product should be included in the dossier. The technical information to be
included in the dossier includes, but is not limited to, schematic diagrams, descriptions,
specifications, analytical methods, CoAs and declarations of compliance to international
standards.
HSA has adopted the ASEAN Guideline on Stability of Drug Product22 for guidance on the
conduct of stability studies for the ASEAN region. Applicants should familiarise
themselves with this guideline prior to submission. Applicants are also reminded that the
ASEAN stability requirements have been implemented since 1st January 2009.
At the time of submission, the minimum stability data required are as follows:
At least 12 months of real time data and 6 months of accelerated data on primary
batches of the drug product, as per the ASEAN guideline;
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Since 1st April 2004, in vivo BE data is required for Prescription Only Medicines (POM) in
oral solid dosage forms.
GDA-2 applications will also require BE 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 was submitted to HSA before 1 April 2004.
Applicants should ensure that the submitted BE study is complete, including all
appendices and data, as per the relevant guidelines. Examples of information to be
included in the report are:
i. Signature of the Principal Investigator to attest the authenticity of the report;
ii. Audit certificate(s), including a BE site inspection report, if available;
iii. Approval letter(s) from the Institutional Review Board/Independent Ethics
Committee and the appropriate drug regulatory agency;
iv. Information about the reference and test products, such as the product name,
strength, dosage form, batch number, manufacturing site, batch size of the test
product, etc.;
v. Certificates of Analysis of the reference and test products used in the BE study,
including the batch size of the test product and manufacturing/expiry date of both
products (where applicable);
vi. Description of the assay methodology and validation; and,
vii. A signed statement confirming that the test product used in the BE study is the
same formulation and is manufactured by the same process as that submitted for
registration.
In instances when the reference product used in the BE study is not the Singapore
reference product, if the criteria listed in section 2 of Appendix 12 are fulfilled, then the
following additional documents must be submitted in support of the application:
i. A comparative table that lists the qualitative composition of both the BE and
Singapore reference products;
ii. Certificates of Analysis of both the reference product used in the BE study and
Singapore reference products, analysed under the proposed specifications for the
generic product;
iii. Comparative dissolution profiles between the BE and Singapore reference
products, as per guideline; and,
iv. Comparative dissolution profiles between the generic and Singapore reference
products, as per guideline.
HSA reserves the right to request for any additional information required to determine the
product interchangeability of the generic product to the Singapore reference product.
SEPTEMBER
Blank Production Batch Records
For new product licence applications, one set of Blank Production Batch Records from
the intended site of manufacture may be requested.
GDAs generally are not required to include non-clinical (animal) and clinical (human) data
to establish a drug products safety and efficacy. Instead, documents required must
demonstrate product interchangeability with the Singapore reference product e.g. in
vivo BE and comparative dissolution studies.
All aspects of the products quality which includes, but is not limited to, the formulation,
site(s) of manufacture, release and shelf life specifications and primary packaging should
be the same as that approved by the drug regulatory agency that issued the proof of
approval.
The complete assessment report and other relevant supporting documents from the
chosen reference agency must be submitted, as tabulated on the next page. The
assessment reports must be unredacted or unedited. Reports from the chosen reference
agency that are obtained from the public domain are deemed unacceptable.
Administrative documents specific to the verification evaluation route that are required at
the time of submission include:
i. 1.4.3 the proposed PI or PIL should be aligned to the currently-registered
Singapore reference product PI or PIL;
ii. 1.9 Official approval letter, or an equivalent document, from the chosen reference
regulatory agency that certify the registration status of the drug product;
iii. 1.13 Official letter declaring that the application submitted to HSA or similar
direction(s) of use, indication(s), dosing regimen(s) and/or patient group(s) have not
been rejected, withdrawn, approved via appeal process23, or pending deferral24 by
any drug regulatory agency, with reasons in each case if applicable;
iv. 1.14 Official letter declaring that the Drug Master File provided is the same as that
submitted to the chosen reference agency, if applicable; and,
v. 1.14 Official letter declaring that all aspects of the products quality intended for
sale in Singapore are identical as that currently approved by the chosen reference
regulatory agency. This includes, but is not limited to, the formulation, site(s) of
manufacture, release and shelf life specifications and primary packaging.
23
Approval via appeal process includes, but is not limited to, the following: approval following negative
opinion, approval following rejection, approval following non-approvable etc.
24
Deferral includes, but is not limited to, the following: non-approvable, approvable, conditional approval,
conditional marketing authorisation, notice of compliance with conditions etc.
complete quality documents for both drug substance and drug product, which
includes:
i. Module 3 dossier as initially submitted to the chosen reference agency; SEPTEMBER
ii. From Sponsor:
- Question and Answers between the chosen reference agency and sponsor
the Answers should include supporting documents used in response to the
Questions;
- All post-approval variations approved by the chosen reference agency up to
the time of submission to HSA, including the application letter for the variation,
supporting documents for the variation, questions and answers between the
reference agency and sponsor and the approval letter for the variation from
the reference agency, if applicable; and,
- Relevant documents required by HSA which have not been submitted to the
chosen reference agency, e.g. stability studies in accordance to ASEAN
Stability Guidelines, Singapore Quality Overall Summary, comparative
dissolution studies, etc;
iii. From DMF Holder, if applicable:
- The initial open and closed parts of the DMF submitted to the chosen
reference agency from the DMF Holder should be provided to HSA, together
with the original Letter of Access;
- Question and Answers between the chosen reference agency and DMF
Holder the Answers should include supporting documents used in response
to the Questions; and,
- All post-approval DMF updates approved by the chosen reference agency up
to the time of submission to HSA, including the application letter for the DMF
update, supporting documents for the DMF update, questions and answers
between the reference agency and sponsor and the approval letter for the
DMF update from the reference agency;
clinical documents, such as BE studies or justification for biowaiver, as initially
submitted to the chosen reference agency with all questions and answers, including
supporting documents, between the reference agency and sponsor; and,
any additional documents to demonstrate product interchangeability with the
Singapore reference product as described in section 17.3.2, where applicable.
Data submitted to HSA must be the same as the data package submitted to the reference
regulatory agencies. Differences between the dossier submitted to HSA and data
reviewed by the reference regulatory agencies will not only delay the processing of the
application, but may also lead to re-routing of the dossier to the abridged evaluation route
if significant undisclosed differences have been discovered.
Registration of Indian generic products may be possible through the CECA scheme
provided that the application meets the eligibility and documentary requirements.
Applicants intending to submit applications via the CECA scheme should refer to
Appendix 13 for more information.
Applicants submitting applications to register biosimilar products must be familiar with the
responsibilities of managing these products throughout their life cycle. Thus, it is
recommended to refer to Appendix 17 or HSAs website25 for more information.
18 APPLICATION TYPES
The product must have been approved by at least one of the following reference
agencies: EU EMA, Australia TGA, US FDA and Health Canada.
Biosimilar products are eligible for the NDA-2 and NDA-3 application types. When
selecting the Product Type in PRISM section 3.2, select Biological Drug.
25
Guidance on Registration of Similar Biological Products in Singapore.
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
A biological product with no suitable Singapore biological reference product will not
qualify for registration as a biosimilar product in Singapore.
19 EVALUATION ROUTES
20 DOCUMENTARY REQUIREMENTS
Table 9 outlines the CTD Modules/Parts required for NDAs submitted for registration of a
biosimilar product:
The administrative documents of the registration dossier for biosimilar products is the SEPTEMBER
same as that described in section 14.1 in Chapter C.
The CTD overviews and summaries are the same as that described in section 14.2 in
Chapter C.
The full quality data (i.e. Module 3 of ICH CTD or Part II of ACTD) should be submitted.
Data submitted should include extensive drug substance and drug product
characterisation and quality comparability data between the biosimilar and the Singapore
biological reference products. The comparability exercise should encompass both drug
substance and drug product and should take into consideration of the following:
the complexity of the molecular structure;
the types of changes introduced in the manufacturing process during development;
and,
the impact on quality, safety and efficacy.
Non-clinical and clinical data generated with the biosimilar product is also required.
The amount of non-clinical and clinical data required for submission will depend on:
the product or class of products;
the extent of characterisation possible undertaken using state-of-the-art analytical
methods;
observed or potential differences between the biosimilar product and the reference
product; and,
the clinical experience with the product class.
Throughout the life cycle of a medicinal product, changes to a products efficacy, quality
and/or safety are likely to occur.
HSA must be notified of any changes to a products safety, efficacy or quality through an
application process i.e. the variation application. Figure 5 below is a schematic diagram
of the variation application routes:
YES MAV-2
There are two types of variation applications: major variation application (MAV) and minor
variation application (MIV). The variations are described as follows:
HSA reserves the right to re-categorise the application type if appropriate. Applicants are
to note that, in PRISM, the re-categorisation of an application (e.g. MIV to MAV-1, MIV-2
to MIV-1 or vice versa) may require withdrawal of the original application. The applicant
will be notified if it will be required to resubmit the application according to the correct
category.
All applications require HSAs approval before the change(s) can be implemented, with
the exception of MIV-2 applications, where the change(s) can be implemented if there is
no objection from HSA within the notification timeline (refer to Appendix 1 for notification
timeline).
The steps to submit an MAV or MIV is similar to submitting an NDA or GDA, as seen in SEPTEMBER
Figure 6 on the next page:
PRE-SUBMISSION
PREPARATION
APPLICATION
NON-ACCEPTANCE / SUBMISSION
WITHDRAWAL
APPLICATION
SCREENING
a
ACCEPTANCE
APPLICATION
EVALUATION
NON-APPROVAL /
WITHDRAWAL
REGULATORY
DECISIONb
a
An acceptance notice will not be sent for MIV-2 applications.
b
A regulatory decision letter will not be sent for MIV-2 applications.
However, each variation application has distinct differences and the applicant should be
familiar with the variation application process in order to facilitate the process.
Applicants are to note that all advice given by HSA will be based on knowledge that is
current at the time of the consultation. Such advice is not binding and does not have a
direct bearing on the eventual outcome of the application concerned.
The applicant may submit a Pre-Submission Inquiry via e-mail if any clarification on SEPTEMBER
submitting an MAV application is needed prior to submission. The e-mail address is:
HSA_MedProd_Registration@hsa.gov.sg. The subject of the e-mail should state, Pre-
submission inquiry, in order for the e-mail to be sent to the relevant officer.
For issues relating to MIV submissions, the applicant should email a completed MIV Filing
and Submission Inquiry Form (Appendix 14) to HSA_MedProd_Registration@hsa.gov.sg.
Upon receipt of an MIV Inquiry Form, an officer will look into the inquiry and respond back
to the named applicant via email with an Inquiry Reference Number. If the MIV is
submitted, then a copy of the Inquiry Form, with the Inquiry Reference Number, should be
included in the submission. The applicant may also opt to fax the completed form to HSA,
but the use of email is strongly encouraged.
Applicants may also request for consultation with HSA. The request should be made in
writing, with the purpose, agenda and proposed date & time for the meeting, and emailed
to HSA_MedProd_Registration@hsa.gov.sg. An officer will respond and facilitate the
arrangement of the meeting.
For a submission under the full evaluation route, the applicant is required to notify HSA
via a pre-submission meeting two months prior to the intended submission date of the
application dossier.
A variation application should comprise of both the submission of the PRISM application
form and the variation application dataset.
Submitting the application through PRISM is similar to that of a NDA or GDA, although
some of the fields in the PRISM application form would not be editable for variation
applications.
The submission of the complete dataset should take place within 2 working days after the
PRISM application submission to prevent delays in processing of the application. The
date of submission will be defined as the date when HSA receives the complete
dataset for the application.
The dataset should be using the CTD format that was selected for the original new
product application.
Applicants are responsible to ensure that all soft copies e.g. scanned documents of
the dossier are legible.
SEPTEMBER
When submitting a CD/DVD, applicants are encouraged to organise the dossier via the
CTD format with folders and subfolders and to include bookmarks to facilitate
screening/reading of the reports.
Applicants must ensure that access to the CD/DVD is not restricted. If so, the applicant
must provide the password(s) to access the CD/DVD contents.
Upon acceptance of the application for evaluation, applicants will be notified if additional
copies of clinical documents (in CD/DVD) will be required.
21.2.2.1 Language
If the foreign document is an original and bears the seal and signature of a recognised
government agency, the document does not require notarisation. Any other type of
document, such as declarations, translations, photocopies, documents lacking an original
signature, etc., must be notarised by a notary public in the country where the document
was issued before the document can be authenticated. The notary public will sign the
document and affix their seal. Notarisation is generally not required for documents
executed 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 in
which they have executed the document;
The place and date of issue of the notarial certificate; and
The signature and seal of the notary.
Applicants are advised to consult the Singapore Embassy/Consulate in the country where
the document originated on local requirements for document legalisation, as these may
deviate from the process as outlined in the preceding paragraph.
Certificates and documents issued in English by drug regulatory agencies do not require
authentication.
Apostille
By international agreement, an apostille can be issued for documents that are to be used SEPTEMBER
in another country that is party to the Hague convention. When an apostille stamp is
attached to a document, it is exempted from all forms of confirmation; i.e. no further
legalisation from a foreign embassy is normally required. Although Singapore at present
is not a party of the Hague Convention, an apostille is acceptable for the authentication of
documents to be submitted to HSA as part of the application dossier.
A certified true copy certifies that the photocopy presented is a true and accurate copy of
the original document. Acceptable certification of documents to support drug product
applications to HSA can be done by the Company Director or Company Secretary as
registered with ACRA or above, or by an independent authority such as a lawyer, notary
public, Commissioner for Oaths/Declarations/Affidavits, Justice of Peace, the original
issuer of the document or Embassy/Consulate. A notarised copy is the same as a
certified true copy.
A certified true copy of approval letters requires certification by the drug regulatory
agency that issued the approval letter, notary public or Singapore 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 available on the drug regulatory agencys
website. In this instance, applicants shall provide the internet address (URL) for validation
by HSA.
The screening process is similar to that for an application for a new medicinal product a
query will be sent to the applicant to address any noted deficiencies in the submission
within a stipulated timeframe.
The evaluation process is similar to that for an application for a new medicinal product.
For applications submitted in PRISM on or after 15 April 2009, applicants can check on
the progress of the evaluation for certain application types and evaluation routes. Table
10 describes the applicable applications and the stages to the evaluation process for
post-approval changes:
Table 10. Variation Applications Applicable for Notification of Stages for Post-Approval Changes
st nd rd th
Stages of Notification to 1 Stage 2 Stage 3 Stage 4 Stage
Applicant SEPTEMBER
Evaluation Status
Application Dossier
Type type Accepted for Active Midway in Evaluation
Evaluation Evaluation Evaluation Completed
Application is Evaluation is
approximately completed for the
midway through application
the evaluation
Application is (provided that Application is now
accepted for When active there were no undergoing the
evaluation evaluation is in prior stop-clocks regulatory decision
Full or progress for which may affect phase, after which
MAV-1 This marks the the application a regulatory
Abridged the evaluation
start of the progress) decision letter*
evaluation would be issued.
timeline Applicants could
expect to receive Applicants could
the first set of still expect further
queries from HSA queries from HSA
during this stage during this stage
* The issuance of a regulatory decision letter would mark the end of the evaluation timeline for a product
application.
Applicants may view the evaluation stage via track@PRISM. Applicants would also be
notified via a system-generated email whenever a status change occurs.
The regulatory decision process is also similar to that for an application for a new
medicinal product. However, a regulatory decision letter will not be issued for MIV-2
applications as these are notifiable changes.
21.5 Fees
The fee structure and quanta are subject to on-going review. For updated information on
fees, please visit the HSA website26.
The screening fee per application is payable at the time of PRISM submission. It is only
applicable for MAV-1 applications. The screening fees are non-refundable once the
application has been successfully submitted via PRISM.
Applicants are advised to ensure that the dataset is compiled according to the required
format. Failure to arrange the submission dossier accordingly will lead to non-acceptance
of the dossier without screening. In these instances, the screening fees will be forfeited.
26
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/
fees.html
Evaluation fees for MAV-1 applications are payable upon acceptance of the MAV-1 for
evaluation.
SEPTEMBER
Evaluation fees for MIV-1 applications are payable upon submission of the application in
PRISM.
Evaluation fees are non-refundable once the application is accepted, regardless of the
final decision by HSA.
With effect from 15 Apr 2009*, the progressive payment scheme was implemented to
allow the payment of evaluation fees by instalments. This is an optional opt-in payment
scheme catered for companies who are under the GIRO payment scheme and only
applicable to the application type listed in the Table 11:
NOTE: To apply for the progressive payment for applications submitted via the full
evaluation route, the applicant must contact HSA via
HSA_MedProd_Registration@hsa.gov.sg to request for a hardcopy progressive
payment application form prior to the submission in PRISM.
For applicants that had chosen the progressive payment scheme, in the event of an
application withdrawal at any point in time during the evaluation stage, any fees that had
been charged, but not yet collected, would still have to be paid; all evaluation fees that
had been paid are non-refundable.
22 MAV-1 SUBMISSIONS
Full dossier: Applies to any MAV-1 variation that has not been approved by
any drug regulatory agency at the time of submission.
Abridged dossier: Applies to any MAV-1 variation that has been evaluated and
approved by at least one drug regulatory agency. The proposed
variation (i.e. the proposed indication(s), dosing regimen(s),
patient group(s) and/or clinical information) should be the same
as that approved by the regulatory agency that issued the proof
of approval.
Verification dossier: Applies to any MAV-1 variation that has been evaluated and
approved by at least two of HSAs 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
The eligibility criteria are different for each evaluation route. Applicants should be familiar
with the criteria for each evaluation route because each route will have different
documentary requirements.
Full evaluation will apply to a major variation that has not been approved by any drug
regulatory agency at the time of submission.
Abridged evaluation will apply to a major variation that has been evaluated and approved
by at least one drug regulatory agency. The proposed variation i.e. the proposed
indication(s), dosing regimen(s), patient group(s) and/or clinical information should be
the same as that approved by the regulatory agency that issued the proof of approval.
If the MAV-1 is for a non-prescription medicine and is submitted via the abridged SEPTEMBER
evaluation route, the applicant may submit a written request for a waiver of clinical data
submission. Eligibility for waiver is subject to the criteria defined in Appendix 5 Guideline
on Submission Requirements for Non-Prescription Medicines. However, HSA reserves
the right to request for the complete clinical data set if it is deemed appropriate.
Similar to an NDA, at least two of HSAs reference drug regulatory agencies must have
evaluated and approved the major variation. However, approval by these reference
regulatory agencies does not obligate HSA to approve the application.
One of the reference drug regulatory agencies must be declared as the primary reference
agency. The chosen primary reference agency is defined as the reference agency for
which the qualifying supporting documents (as outlined in this guidance) will be submitted
and which approved the strictest indication(s), dosing regimen(s), patient groups(s)
and/or direction(s) for use among the two HSA reference drug regulatory agencies which
approved the variation.
The proposed indication(s), dosing regimen(s), patient group(s) and/or direction(s) for use
should be the most stringent amongst those approved by the reference regulatory
agencies.
For a product with a proposed indication that has been designated as an Orphan Drug by
at least one reference agency or a product that has been approved by at least one
reference agency via an accelerated/fast-track approval, approval under exceptional
circumstances or equivalent approval process, the applicant should consult HSA on the
eligibility of such a product through the verification route prior to submission.
Table 12 outlines the CTD Modules/Parts required for MAV-1s submitted under each
evaluation route:
If the proposed MAV-1 is related to non-clinical data, non-clinical summary and non-clinical overview as well
as relevant study reports is required.
#
Non-clinical overview only, if applicable.
For MAV-1 applications, in order to ensure that the dossier is complete, application
checklists for both ICH CTD and ACTD dossiers are provided in Appendix 2B and 3B,
respectively. Each checklist states the required documents for each dossier type and
application type. Refer to the specific Appendices for more details.
The three evaluation routes for an MAV-1 share the same documentary requirements for
CTD Module 1/Part I. The documents required are:
i. 1.1 Comprehensive Table of Contents;
ii. 1.2 Introduction including the Table of Amendment Details of PRISM section
0.5;
iii. 1.3 PRISM application form;
iv. 1.4 Labelling, Package Insert and Patient Information Leaflet both the proposed
and currently approved Singapore product labels and PI/PIL are required. For the
proposed labelling/PI/PIL, a pristine and an annotated version (which highlights the
changes made to the currently approved labelling) are required;
v. 1.5 Approved SPC/PI/PIL from the drug regulatory agency that issued the proof of
approval and from each of HSAs reference drug regulatory agencies (where
applicable);
vi. 1.6 Assessment Report from Reference Agencies only for verification route
(see section 22.2.5.3);
vii. 1.8, 1.9 Proof of Approval for an MAV-1, the official approval letter(s) must
contain information on the requested Singapore variation. For the verification
evaluation route, the approval letters issued by the relevant reference agencies
should be submitted;
viii. 1.13 Declaration on rejection, withdrawal and deferral; and,
ix. 1.15 Registration Status in Other Countries.
Quality documents (Module 3/Part II) are not required for MAV-1 applications.
Each evaluation route will have different non-clinical and clinical documentary
requirements. Refer to section 22.2.5 for more information.
Risk management plans (RMP) submitted to EMA, risk evaluation and mitigation
strategies (REMS) submitted to US FDA, and/or other relevant documents pertaining to
such purposes should be included, where available. The need to implement a risk
management plan in Singapore would be assessed on a case-by-case basis during the
review process.
The complete assessment report and other relevant supporting documents from the
chosen primary reference agency must be submitted, as tabulated below. The
assessment reports from the primary reference agency must be unredacted or unedited.
Reports obtained from the public domain are deemed unacceptable.
All of the data submitted to HSA must be the same as the data package submitted to the
reference regulatory agencies. Differences between the dossier submitted to HSA and
data reviewed by the reference regulatory agencies will not only delay the processing of
the application, but may also lead to re-routing of the dossier to the abridged evaluation
route if significant undisclosed differences have been discovered.
23 MAV-2 SUBMISSIONS
Reclassification may also be undertaken when experience gained shows that there is a
need to supervise the use of a product i.e. from GSL to P or POM.
ii. The product has been marketed for a period of time sufficient to establish a post-
marketing adverse event profile; and,
iii. The products safety profile gives no cause for concern during the marketing period. SEPTEMBER
Applicants who wish to submit a request for reclassification of a medicinal product shall
provide justification based on the following information:
i. The forensic classification and approved indication(s) and dosing regimen(s) of the
product in the UK, US, Canada and Australia;
ii. The period of product registration in Singapore, UK, US, Canada and Australia, with
specific information on its forensic classification (i.e. POM, P and/or GSL) and
duration of sale in that classification;
iii. The period of actual product sale in Singapore;
iv. The rationale for requesting a change in the forensic classification;
v. Patient exposure of the product and its safety profile based on worldwide
spontaneous adverse drug reaction reports, data from post-marketing surveillance
studies, clinical trials, published literature and locally reported adverse drug
reactions; and,
vi. Potential problems and hazards arising from the inappropriate use of the product.
A me-too reclassification will be considered if an analogous product with the same active
ingredient and intended use has been reclassified to the requested forensic classification.
24 MIV SUBMISSIONS
Applicants should be familiar with the guidelines before submitting minor variation
applications (MIVs). The guidelines and documentary requirements are described in
Appendix 15 (chemical) and 16 (biologics).
With effect from 1 July 2011, MIV-1 changes should be grouped together as one
application when these changes are consequential changes. A consequential change is
regarded as a change that is unavoidable and is a direct result of another change, not
simply a change that occurs at the same time. HSA reserves the right to split any MIV-1
application with non-consequential changes into separate MIV applications.
HSA also reserves the right to re-categorise the MIV if deemed appropriate.
NOTE: Applicants are encouraged to fax or email the MIV Filing and Submission
Inquiry Form in Appendix 14 for any issues regarding MIV filing.
Applicants should ensure that all conditions and documentary requirements for the MIV
have been fulfilled prior to submission. For an MIV with multiple variations, all of the
requirements for each individual variation must be met. Applicants are advised to refer to
Appendix 15 or 16 for information on whether to submit documents in hardcopy or
softcopy.
Any undisclosed variation(s) embedded in the submitted data, including any flow-on
changes, will not be considered. Evaluation will be based on the data relevant to the
proposed variation(s), unless HSA specifically requests for additional information.
HSA only accepts applications on-line via PRISM. Applicants are advised to visit the
prism@hsa27 webpage for further details on PRISM.
NOTE: NEW applicants must have a CRIS account in order to register medicinal
products via PRISM. For information on setting up a CRIS account, refer to the
following weblink:
http://www.hsa.gov.sg/publish/hsaportal/en/services/cris.html
A separate Product Licence, and therefore a separate application, would be required for
each pharmaceutical dosage form and strength of the medicinal product. Separate
application forms are also required for the following (see Example 1):
Powders for injection containing different amounts of drug substance per container;
Concentrates for reconstitution labelled with the actual amount of drug substance
before reconstitution; and,
All single-use pre-filled syringes containing different amount of active ingredient in
each syringe.
Example 2 on the next page are examples of injectable products which are allowed to be
registered under one product licence (as pack sizes):
27
http://www.hsa.gov.sg/publish/hsaportal/en/services/prism.html
Example 2. Injectable products which are allowed to be registered under one product
licence (as pack sizes):
SEPTEMBER
Examples Labelled strength before Application type
reconstitution
Solution for Injection 2mg/mL in a vial containing Submit as one application with two pack
1 mL of the solution sizes (i.e., 1 mL and 2 mL)
2mg/mL in a vial containing
2 mL of the solution
Concentrate 2mg/mL: presented in 5 mL Submit as one application with two pack
vial and 10 mL vial sizes (i.e., 5 mL and 10 mL)
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 by
a responsible person in the company/organisation that owns the medicinal product before
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 and
Business Registration number (UEN) will be automatically populated. If there is a direct
telephone and/or fax number, input it into this section to ensure no communication delays
between HSA and the applicant.
The company bears full responsibility for ensuring that all available and relevant
information is submitted in support of an application. For every successful application for
registration 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.
The person named in this section should be a permanent staff of the company and
residing in Singapore. If the applicant is an external party engaged by the applicant
company to submit the application on their behalf (i.e. consultant), an original letter of
authorisation from the applicant company must be submitted (refer to section 14.1
Administrative 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 screenshot on
the next page:
SEPTEMBER
Company address
may be entered
Care should be taken to ensure that the contact details are entered correctly to ensure no
communication delays between HSA and the applicant. Applicants are advised to notify
HSA immediately via amend@PRISM28 (select Amend Applicants Details for licences
and applications) if there is any change to this PRISM section, especially to the contact
details.
From this point on, any mention of the word applicant in this guidance document will
refer to the person named within this PRISM section.
In this PRISM section, enter specific details of the application, such as the application
type, dossier type, format type and any reference product(s), if applicable. A screenshot
of PRISM section 3 is shown below:
28
http://www.hsa.gov.sg/publish/hsaportal/en/services/prism/drugs.html
Note:
After the application has been submitted, if the type of application is selected incorrectly
and it needs to be changed
within the same application type (e.g. from NDA-2 to NDA-3), then HSA will notify
the applicant and change the application form on behalf of the applicant at the point
of acceptance of the application; 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 correct
application type.
HSA reserves the right to re-categorise the application type when appropriate.
Input either Chemical Drug for chemical drug product or Biological Drug for biologic
drug products. Please note that once the product type is set, it cannot be changed
throughout the entire products life cycle.
Applicants are advised to contact HSA, via pre-submission inquiry or meeting, as stated
in section 5.3, when in doubt on whether the drug product is considered a chemical or
biologic product.
For all GDA applications, applicants need to specify the Singapore Reference Products
SIN number, which can be obtained by searching HSAs online database29. If a GDA-2
application is not submitted at the same time as a GDA-1 application, specify both the
Singapore Reference Products and the GDA-1 products SIN numbers.
For NDA-3 applications, if the application is not submitted at the same time as an NDA-1
or NDA-2 application, input the SIN number of the Singapore-registered NDA-1 or NDA-
2.
This refers to the three evaluation routes as mentioned in section 5.2 of this guide.
29
http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=load
Only one option can be selected from the drop-down menu full, abridged or verification.
For applications under the Special Scheme for registration of Indian generic products, SEPTEMBER
choose the Verification CECA option.
HSA reserves the right to re-categorise the dossier type when appropriate. The applicant
will be informed if re-categorisation is necessary.
Indicate whether the dossier format is ICH CTD or ACTD. Once the format type has been
set in PRISM, it cannot be changed throughout the entire products life cycle.
Applicants are expected to organise the documents into the respective CTD sections
before submitting the dossier to HSA. Explanatory notes on the registration dossier
format can be found in section 6.2.
The Product Name is the products trade name that is shown on the product labelling.
From this point on, any mention of the term product labels or product labelling in this
guidance document will refer to the inner label, outer carton, package insert (PI) and/or
patient information leaflet (PIL) of the product.
If the proposed product name is not acceptable, the applicant will be informed of the
reasons, and will be asked to amend it.
Applicants are advised to use the same format for the product labelling. However, the
International Non-proprietary Name (INN) or common name of the active substance(s)
may be used when referring to the active ingredient(s)s properties in the PI.
The product strength represents the amount of the active substance in the
pharmaceutical 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 products where it would be difficult to include the strength in the product name (e.g.
vaccines, total parental nutrition solution, haemofiltration solution, etc), the product
strength may be omitted from the product name. SEPTEMBER
For specific pharmaceutical dosage forms, there are additional points to take note of as
seen in the table below:
The Product Formula is a list of all of the active substance(s) and excipients (including
water) that are present in the final pharmaceutical dosage form, as seen in the
screenshot below:
Proper or commercial names for ingredients, such as printing inks or colourants, are
permissible but internal abbreviations, acronyms or codes for any ingredient are not
acceptable. The grade for each ingredient should be specified e.g. in-house, BP, USP,
Ph. Eur., etc.
Full compositions of all ingredients (e.g. colourants, flavouring agents, etc.) used in the
product should be stated in the Product Formula, and their uses differentiated as stated
below.
Ingredients relating to the pharmaceutical dosage form, such as tablet film coating or SEPTEMBER
capsule shell, should be indicated within parentheses before the ingredient name, as
shown in the following screenshot:
Printing ink
If the product contains proprietary ingredients, relating to the dosage form (such as tablet
film coating or capsule shell), this information should be captured in PRISM as shown in
Example 3.
Example 3. Entry of proprietary ingredients relating to the dosage form for Product XYZ:
Product XYZ
SEPTEMBER
If the product contains ingredients relating to a particular portion of the finished drug
product, such as powder (active substance) and solvent (solution for reconstitution) or a
multi-layered tablet, the portion of the drug product should be stated in parentheses
before the ingredient name of the excipients see Examples 4 and 5:
Excipient in powder
Excipient in solvent
Excipients in Y layer
Excipients in Z layer
salt, the quantity stated should reflect that stated on the product labelling, and should be
clearly written in the following format (see table below and Examples 6 to 8):
SEPTEMBER
Eg Description Product strength stated Format of product strength
on product label to be stated in PRISM
6 Strength on the label refers 30mg Active Substance Active Substance phosphate
to the base form of the 32mg eqv Active Substance
active substance.
7 Strength on the label refers 30mg Active Substance Active Substance 28mg eqv
to the salt form of the phosphate Active Substance phosphate
active substance.
8 Strength refers to neither 30mg Active Substance Active Substance 28mg eqv
the base nor salt form of sodium Active Substance phosphate
the active substance. 32mg eqv Active Substance
sodium
Example 8. Strength on label refers to neither base or salt form of active substance:
SEPTEMBER
Information on substances which were removed during the manufacturing process, such
as water or ethanol which evaporates during drying, should be included in the Product
Formula, but with the strength stated as qs.
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.
SEPTEMBER
If the answer is Yes, the following information must be inserted as per the format below:
the type of product derived from blood and 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.
NOTE: additional information is required when human plasma-derived products are used.
Refer to Appendix 10 for details on the data requirements for submission.
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.
SEPTEMBER
NOTE: refer to Appendix 11 for details on the data requirements for submission.
Indicate the WHO ATC code for each distinct therapeutic indication proposed for a
product, if available. Applicants may refer to the WHO Collaborating Centre for Drug
Statistics Methodology30 for the ATC Code and more information.
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 each
form is considered distinct e.g. effervescent powder, powder for reconstitution,
modified-release tablet and gastro-resistant capsule.
In certain cases, the dosage form may also include information about the container
closure system e.g. pre-filled syringe, spray pump and pressurised container.
30
http://www.whocc.no/
This section refers to the container immediately enclosing the dosage form. Information
should be specific, including the type of material(s) used, colour, size, etc. For example,
Type I 1mL amber glass vial and Transparent PVC/PVdC blister with Alu foil should be
entered instead of Amber glass vial and PVC/PVdC blister, respectively.
If a sample pack is to be registered, include (sample) at the end of the CCS description.
This section refers to the quantity/amount of the dosage form per container closure SEPTEMBER
system. For example, 10 tablets/blister, 5ml/vial and 15g/tube may be entered.
This section refers to the proposed shelf life of the drug product, which should be
supported by stability data. If there is more than one component in a drug product (e.g.
powder for injection and diluent as a composite pack) and each component has a
different shelf life, the shorter shelf life is to be used as the shelf life of the composite
pack. HSA reserves the right to amend the proposed shelf life after review of the stability
data submitted in the dossier.
This section refers to the proposed storage condition of the drug product for example,
store below 25C, do not freeze, keep away from light, etc which should 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.
This section refers to the number of container closure systems in each commercial pack
of the product. For example, for a box of 50 tablets packed as 5 blister strips of 10 tablets
in each strip, the Pack Size should be entered as 5.
NOTE: Click
Save after
each complete
CCS entry.
Thereafter, to
enter a new
CCS, click
New first.
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 be
provided and supported by stability data. The information should be inserted in PRISM
sections 4.7.6 and 4.7.7, respectively:
State the forensic classification proposed for the drug product in Singapore. SEPTEMBER
HSA reserves the right to approve the product under a different forensic classification, as
deemed appropriate.
Applicants are required to provide information on the registration status of the application
in other countries at the time of submission. A screenshot of PRISM section 4.9 is given:
For each country, the applicant must state the application status, status date and forensic
classification (if applicable). For all HSAs reference agencies, the applicant must state
the application status, status date, application details and forensic classification. This is
described in Table 13 on the next page.
The screenshot below displays some entries into PRISM section 4.9:
i. Select European Union under 4.9.1 State Country and specify the type of
application submitted to the agencies (Centralised, Decentralised or Mutual
Recognition Procedure) under 4.9.4 Application Details; and/or, SEPTEMBER
ii. For applications approved via Decentralised or Mutual Recognition Procedure,
either state All EU countries or list the EU countries which participated in the
procedure under 4.9.4. Application Details; and,
iii. For applications approved via Decentralised or Mutual Recognition Procedure,
state the EU country which acted as the Reference Member State (RMS) and
Concerned Member State (CMS) under 4.9.4 Application Details.
The applicant is required to update HSA on the registration status of any pending
applications in other countries while pending evaluation by HSA. The applicant shall
inform HSA of any rejection, withdrawal or deferral of any application and provide details
of the reason(s) once it becomes known.
In the event that the PRISM text space does not allow input of full details of the
indication(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 (Supporting
Attachments) and in hardcopy in section 1.15 of the CTD Module 1/Part I. The document
should be in the format as seen in Table 7 in this guidance.
Input the full name and address of the legally registered owner of the product formulation,
i.e. the drug product.
Enter information on the various manufacturers involved in all aspects of producing the
final drug product. Information to be entered include:
Manufacturer type involved either in Active Substance or Finished Product
manufacture;
Manufacturers name;
Manufacturing operation involved in bulk production, packing, labelling or any
combination of the three; and,
Manufacturers address input both the manufacturing site and office (i.e.
headquarters) address.
SEPTEMBER
All manufacturers of the active substance(s), drug product (inclusive of diluent packed
and sold together with the drug product), and primary/secondary packaging sites must be
declared.
When entering the details of the Active Substance Manufacturer, select the active
substance(s) that is manufactured by that particular manufacturer from the drop-down list
in section 5.8 of the PRISM application form. After selecting the Active Substance, click
the Save Substance button; this may be repeated for other substances if the
Manufacturer produces multiple substances for the drug product. Once complete, click
the Save Manufacturer button to save the entire section for that Active Substance
Manufacturer:
SEPTEMBER
Entries of finished product manufacturers would include not only manufacturers of the
finished product but also secondary packagers and manufacturers of diluents that are
packed and sold together with the drug product.
After entering the details of the Finished Product Manufacturer, click the Save
Manufacturer button to save the entire section for that Finished Product Manufacturer:
SEPTEMBER
NOTE: ALL Manufacturers names and addresses should be consistent throughout all
of the documents submitted in the application, i.e. CPPs, GMP certificates, Letters of
Authorisation, Module 3/Part II of the CTD and so forth.
Enter the name, site/plant address and office address of the company responsible for the SEPTEMBER
final batch release of the drug product in the exporting country. The Finished Product
Manufacturer(s), which the Batch Releaser is releasing the product from, must also be
specified.
After selecting the Finished Product Manufacturer that this particular Batch Releaser is
releasing the products from (PRISM section 6.4), click the Save Manufacturer button to
save that manufacturer to that batch releaser.
Click the Save Batch Releaser button to save the entire section for that Batch Releaser.
It is also possible to have one Batch Releaser releasing products from two finished
product manufacturers as well as multiple Batch Releasers see Examples 11 and 12 on
the next page:
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Page 100 of 102
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE APRIL 2011
Example 11. One Batch Releaser responsible for multiple Finished Product
Manufacturers.
SEPTEMBER
Example 12. Mulitple Batch Releasers responsible for batch release of the final product.
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Page 101 of 102
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE APRIL 2011
Before completion of the on-line application, applicants must attach all documents relating SEPTEMBER
to 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 or submit
soft copies of the documents in a CD/DVD.
NOTE: Acceptance of the dossier for evaluation does not constitute acceptability
of the data provided in the dossier. Acceptability of the data can only be
determined during evaluation of the application.
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Page 102 of 102
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE APRIL 2011
LIST OF APPENDICES
APPENDIX 1 Target Processing Timelines
APPENDIX 13 Guideline on Submission for Indian Generic Products Under the CECA
Scheme
APPENDIX 16 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for Biologics
HSA shall endeavour to meet the target processing timelines for all submitted
applications. Applicants should ensure that the dossiers are complete before submission.
Incomplete dossiers and untimely responses to queries will cause unnecessary delays to
the registration process and thus, will have a negative impact on the target processing
timelines.
1 SCREENING TIMELINE
The target processing timeline for screening of the dossiers (NDA, GDA, MAV-1, MAV-2,
MIV-1) is 25 working days before the first communication, in the form of an Input
Request or acceptance/non-acceptance notification, is issued. The target processing
timeline for screening of a dossier submitted under the CECA scheme is 14 working days
(refer to Appendix 13).
The screening timeline begins from the date of the dossier submission, which should be
within 2 working days after PRISM submission to prevent delays in processing of the
application. The date of submission will be defined as the date when HSA receives the
complete dataset for the application (including all hard copies of original signed
documents and CD/DVD- ROMs).
2 EVALUATION TIMELINE
The target processing timeline for evaluation of an application is the period from the date
of acceptance to issuance of a regulatory decision letter, excluding all stop-clocks. The
target timelines for the various evaluation routes are as follows:
For MIV-2 applications, the applicant can implement the proposed change(s) if HSA does
not raise any objection within 40 working days from the date of submission of the
complete dataset for the application. The complete dataset includes the PRISM
application submission, all hard copies of original signed documents and the supporting
documents required for the proposed changes.
If queries are raised on the completeness of the dataset, a stop-clock time will apply. This
stop-clock time is to be excluded from the 40 working days timeline.
4 STOP-CLOCK
Stop-clocks can occur during the screening and evaluation stages of the application. The
stop-clock starts when HSA requests for clarification or additional information with regard
to a product application. The stop-clock period ends when HSA receives a complete and
satisfactory response to the query.
NOTE: the stated processing timelines are intended for reference only and do not
necessarily represent the actual processing timelines for the applications.
Applicants should refer to track@PRISM for updates on application status and
processing time.
This Application Checklist should be used to ensure submission of a complete dataset in the ICH Common Technical Dossier (ICH CTD) format
for NDA and GDA applications only.
To use this Checklist, check against the dossier and application type for your submission.
Note:
Cells with indicates that the document shown in the second column of the same row is mandatory for the selected application type and
evaluation route.
Cells with with an asterisk * indicates that the document shown in the second column of the same row may be optional depending on the
application type/product/change concerned.
Cells without indicates that the document shown in the second column of the same row is not required for the selected application type and
evaluation route.
Please refer to the Guidance on Medicinal Product Registration in Singapore and the ICH technical guidance for explanatory notes on the
preparation of documents for a submission in ICH CTD format.
Section Documents
NDA GDA
Section Documents
NDA GDA
Section Documents
NDA GDA
Section Documents
NDA GDA
Section Documents
NDA GDA
Section Documents
NDA GDA
Declaration letter should be provided if the trade name of the product registered in the
country which issued the proof of approval is different from that proposed in Singapore
*: Proof of approval is not required for GDAs undergoing abridged evaluation for
finished product manufactured (up to primary packaging) in Singapore
1.9 Proof of Approval from HSAs reference regulatory agencies
(NDA: 2 reference regulatory agencies, GDA: 1 reference regulatory agency)
Please specify issuing agencies:
__________________________________________________
Section Documents
NDA GDA
This letter authorises the local applicant firm to apply for and be the Product
Licence Holder for a specific medicinal product
1.10.2 Authorisation Letter from Product Owner to the Manufacturer(s)
This letter authorises the specified manufacturer to produce, pack and/or label
the drug product intended for Singapore
If there are multiple drug product manufacturers, the applicant may opt to
submit one authorisation letter which clearly states all of the manufacturers
(names and addresses) and their responsibilities related to the drug product
For biologic drug products, an additional authorisation letter from the Product
Owner to the Drug Substance Manufacturer is required
1.10.3 Authorisation Letter from Product Owner to the Batch Releaser
This letter authorises the specified company to test and batch release the drug
product
GMP certification/proof of GMP compliance for each finished product manufacturer
1.11
inclusive of secondary packer(s)
For biologics: GMP certification/proof of GMP compliance for each drug substance
manufacturer must be provided
For GDA Verification CECA: GMP certificate/ proof of GMP compliance and the latest
inspection report as issued by the reference agency should be submitted
Proof of GMP compliance must not expire within 6 months from the time of submission
to HSA
Diluents used for reconstituting the drug product and are packaged together with the
drug product will be considered as part of the final drug product; Manufacturer(s) of the
supplied diluent(s) will follow the same requirements applicable to the drug product
e.g. proof of GMP compliance
The names and addresses of manufacturer(s) / repacker(s) should be consistent with
information provided in application form
If applicable, application for GMP Conformity Assessment should be submitted together
with the product application
1.12 Patent declaration form
Section Documents
NDA GDA
The Patent Declaration form is required for each NDA and GDA
Under Applicant Particulars, name & address of the local applicant firm to be stated
Under Product Particulars, the product name is stated and it should be consistent with
that stated in PRISM, the application form, all product labelling and all other relevant
documents in the dossier
Under Declaration, the patent declaration must be signed by the Company Director,
Company Secretary as registered with ACRA, or equivalent.
Evidence of authorisation (e.g. ACRA printout) should be submitted together with the
declaration.
1.13 Declaration on rejection, withdrawal and deferral
Declaration that all aspects of the Singapore products quality are identical to that
1.14
currently approved by the chosen primary reference regulatory agency.
Official letter declaring that the Drug Master File provided is the same as that submitted
to the primary reference agency, if applicable.
Registration Status in Other Countries as separate attachment in PRISM under [7]
1.15
Supporting Attachments
For NDA & GDA, registration status should be entered into PRISM section 4.9; In the
event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered; The full details
should then be attached in softcopy (PDF) in this PRISM section (supporting
attachments)
Section Documents
NDA GDA
Module 3 Quality
Section Document
NDA GDA
For verification dossier The submission should include Module 3 dossier as originally
submitted to the reference agency, and any documentations submitted to the same reference
agency in subsequent variations to the quality aspects of the product.
3.1 Module 3 Table of Contents
3.2 Body of Data
3.2.S Drug Substance (Active Substance)
If DMF is submitted, refer to main Guidance, sections 14.3.1 & 17.3.1
If CEP (Certificate of Suitability) is submitted, waiver of documents for this
section can be granted except for S4.1, S4.2 & S4.4.
The manufacturers info provided in the CEP is consistent with the
information provided in the application form.
Please note that information not included in the CEP would have to be
supported by substantial data (e.g. S6 & S7 is required if no retest period
and/or packaging is stated in the CoA).
To take note of the validity of the certificate.
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.1.3 General Properties
3.2.S.2 Manufacture
3.2.S.2.1 Manufacturer(s)
Description of Manufacturing Process and Process
3.2.S.2.2
Controls
Section Document
NDA GDA
Section Document
NDA GDA
Section Document
NDA GDA
Section Document
NDA GDA
Section Document
NDA GDA
Section Document
NDA GDA
Section Document
NDA GDA
3.2.A Appendices
3.2.A.1 Facilities and Equipment
3.2.A.2 Adventitious Agents Safety Evaluation * *
3.2.A.3 Novel Excipients * *
3.2.R Regional Information/Requirements
Checklist for Human Blood Product with required supporting
3.2.R.1
documents * * * * *
For human derived materials, please indicate Yes in PRISM
section 4.3a and complete with relevant information
3.2.R.2 TSE Checklist with required supporting documents
* * * * *
For animal derived materials, please indicate Yes in PRISM
section 4.3b and complete with relevant information
3.2.R.3 Product Interchangeability (Bioequivalence Study Reports)
* * *
Reference product used in Bioequivalence study is the Singapore
Reference Product and uses the same site of manufacturing.
If not, refer to Appendix 12 for the bridging data required
If BE study not required, justification for viowavier is required, with
supporting documents
3.2.R.4 Blank Production Batch Record * * * * *
3.3 List of Literature References
Section Documents
NDA GDA
Section Documents
NDA GDA
Section Document
NDA GDA
This Application Checklist should be used to ensure submission of a complete dataset in the ICH Common Technical Dossier (ICH CTD) format
for MAV applications only.
To use this Checklist, check against the dossier and application type for your submission.
Note:
Cells with indicates that the document shown in the second column of the same row is mandatory for the selected application type and
evaluation route.
Cells with with an asterisk * indicates that the document shown in the second column of the same row may be optional depending on the
application type/product/change concerned.
Cells without indicates that the document shown in the second column of the same row is not required for the selected application type and
evaluation route.
Please refer to the Guidance on Medicinal Product Registration in Singapore and the ICH technical guidance for explanatory notes on the
preparation of documents for a submission in ICH CTD format.
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
Declaration letter should be provided if the trade name of the product registered in the country
which issued the proof of approval is different from that proposed in Singapore
*: Proof of approval for MAV-2 should be in the form of documentation which proves that that
product had been reclassified (for specific indication(s) or dosing regimen(s)) in the UK, US,
Canada and/or Australia. This is not required for me-too reclassification.
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
4.2.3.3 Genotoxicity *
4.2.3.4 Carcinogenicity *
4.2.3.5 Reproductive and Developmental Toxicity *
4.2.3.6 Local Tolerance *
4.2.3.7 Other Toxicity Studies *
4.3 List of Literature References *
Section Document
MAV-1 MAV-2
This Application Checklist should be used to ensure submission of a complete dataset in the ASEAN Common Technical Dossier (ACTD) format
for NDA and GDA applications only.
To use this Checklist, check against the dossier and application type for your submission.
Note:
Cells with indicates that the document shown in the second column of the same row is mandatory for the selected application type and
evaluation route.
Cells with with an asterisk * indicates that the document shown in the second column of the same row may be optional depending on the
application type/product/change concerned.
Cells without indicates that the document shown in the second column of the same row is not required for the selected application type and
evaluation route.
Please refer to the Guidance on Medicinal Product Registration in Singapore and the ASEAN Guidance on ACTD for explanatory notes on the
preparation of documents for a submission in ACTD format.
Section Documents
NDA GDA
Section Documents
NDA GDA
Section Documents
NDA GDA
Section Documents
NDA GDA
Section Documents
NDA GDA
Section Documents
NDA GDA
Declaration letter should be provided if the trade name of the product registered in the
country which issued the proof of approval is different from that proposed in Singapore
*: Proof of approval is not required for GDAs undergoing abridged evaluation for
finished product manufactured (up to primary packaging) in Singapore
1.9 Proof of Approval from HSAs reference regulatory agencies
(NDA: 2 reference regulatory agencies, GDA: 1 reference regulatory agency)
Please specify issuing agencies:
__________________________________________________
Section Documents
NDA GDA
This letter authorises the local applicant firm to apply for and be the Product
Licence Holder for a specific medicinal product
1.10.2 Authorisation Letter from Product Owner to the Manufacturer(s)
This letter authorises the specified manufacturer to produce, pack and/or label
the drug product intended for Singapore
If there are multiple drug product manufacturers, the applicant may opt to
submit one authorisation letter which clearly states all of the manufacturers
(names and addresses) and their responsibilities related to the drug product
For biologic drug products, an additional authorisation letter from the Product
Owner to the Drug Substance Manufacturer is required
1.10.3 Authorisation Letter from Product Owner to the Batch Releaser
This letter authorises the specified company to test and batch release the drug
product
GMP certification/proof of GMP compliance for each finished product manufacturer
1.11
inclusive of secondary packer(s)
For biologics: GMP certification/proof of GMP compliance for each drug substance
manufacturer must be provided
For GDA Verification CECA: GMP certificate/ proof of GMP compliance and the latest
inspection report as issued by the reference agency should be submitted
Proof of GMP compliance must not expire within 6 months from the time of submission
to HSA
Diluents used for reconstituting the drug product and are packaged together with the
drug product will be considered as part of the final drug product; Manufacturer(s) of the
supplied diluent(s) will follow the same requirements applicable to the drug product
e.g. proof of GMP compliance
The names and addresses of manufacturer(s) / repacker(s) should be consistent with
information provided in application form
If applicable, application for GMP Conformity Assessment should be submitted together
with the product application
1.12 Patent declaration form
Section Documents
NDA GDA
The Patent Declaration form is required for each NDA and GDA
Under Applicant Particulars, name & address of the local applicant firm to be stated
Under Product Particulars, the product name is stated and it should be consistent with
that stated in PRISM, the application form, all product labelling and all other relevant
documents in the dossier
Under Declaration, the patent declaration must be signed by the Company Director,
Company Secretary as registered with ACRA, or equivalent.
Evidence of authorisation (e.g. ACRA printout) should be submitted together with the
declaration.
1.13 Declaration on rejection, withdrawal and deferral
Declaration that all aspects of the Singapore products quality are identical to that
1.14
currently approved by the chosen primary reference regulatory agency.
Official letter declaring that the Drug Master File provided is the same as that submitted
to the primary reference agency, if applicable.
Registration Status in Other Countries as separate attachment in PRISM under [7]
1.15
Supporting Attachments
For NDA & GDA, registration status should be entered into PRISM section 4.9; In the
event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered; The full details
should then be attached in softcopy (PDF) in this PRISM section (supporting
attachments)
Part II Quality
Section Document
NDA GDA
For verification dossier The submission should include Part II of the dossier as originally
submitted to the reference agency, and any documentations submitted to the same reference
agency in subsequent variations to the quality aspects of the product.
A Table of Contents of Part II
B Singapore Quality Overall Summary (QOS) & QOS in other format, if available
C Body of Data
Drug Substance (Active Substance)
If DMF is submitted, refer to main Guidance, sections 14.3.1 & 17.3.1
If CEP (Certificate of Suitability) is submitted, waiver of documents for this section can
be granted except for S4.1, S4.2 & S4.4.
The manufacturers info provided in the CEP is consistent with the information
provided in the application form.
Please note that information not included in the CEP would have to be supported by
substantial data (e.g. S6 & S7 is required if no retest period and/or packaging is stated
in the CoA).
To take note of the validity of the certificate.
S1 General Information
S1.1 Nomenclature
S1.2 Structure
S1.3 General Properties
S2 Manufacture
S2.1 Manufacturer(s)
S2.2 Description of Manufacturing Process and Process Controls
Section Document
NDA GDA
Section Document
NDA GDA
Section Document
NDA GDA
Section Document
NDA GDA
Section Document
NDA GDA
Section Document
NDA GDA
Section Document
NDA GDA
Section Documents
NDA GDA
Section Documents
NDA GDA
D3.3 Distribution
D3.4 Metabolism
D3.5 Excretion
D3.6 Pharmacokinetic Drug Interactions (non-clinical)
D3.7 Other Pharmacokinetic Studies
D4 Toxicology
D4.1 Single-Dose Toxicity
D4.2 Multiple-Dose Toxicity
D4.3 Genotoxicity
D4.4 Carcinogenicity
D4.5 Reproductive and Developmental Toxicity
D4.6 Local Tolerance
D4.7 Other Toxicity Studies
E List of Key Literature References
Section Document
NDA GDA
Section Document
NDA GDA
This Application Checklist should be used to ensure submission of a complete dataset in the ASEAN Common Technical Dossier (ACTD) format
for MAV applications only.
To use this Checklist, check against the dossier and application type for your submission.
Note:
Cells with indicates that the document shown in the second column of the same row is mandatory for the selected application type and
evaluation route.
Cells with with an asterisk * indicates that the document shown in the second column of the same row may be optional depending on the
application type/product/change concerned.
Cells without indicates that the document shown in the second column of the same row is not required for the selected application type and
evaluation route.
Please refer to the Guidance on Medicinal Product Registration in Singapore and the ASEAN Guidance on ACTD for explanatory notes on the
preparation of documents for a submission in ACTD format.
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
Declaration letter should be provided if the trade name of the product registered in the country
which issued the proof of approval is different from that proposed in Singapore
*: Proof of approval for MAV-2 should be in the form of documentation which proves that that
product had been reclassified (for specific indication(s) or dosing regimen(s)) in the UK, US,
Canada and/or Australia. This is not required for me-too reclassification.
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
Section Documents
MAV-1 MAV-2
D3.3 Distribution *
D3.4 Metabolism *
D3.5 Excretion *
D3.6 Pharmacokinetic Drug Interactions (non-clinical) *
D3.7 Other Pharmacokinetic Studies *
D4 Toxicology
D4.1 Single-Dose Toxicity *
D4.2 Multiple-Dose Toxicity *
D4.3 Genotoxicity *
D4.4 Carcinogenicity *
D4.5 Reproductive and Developmental Toxicity *
D4.6 Local Tolerance *
D4.7 Other Toxicity Studies *
E List of Key Literature References *
Section Document
MAV-1 MAV-2
Section Document
MAV-1 MAV-2
Study reports of pivotal or relevant clinical trials (appendices & tables are required
upon request by HSA)
E6 Reports of Post-marketing Experience * * *
E7 Case Report Forms and Individual Patient Listings (required upon request by HSA)
F List of Key Literature References
G Other Supporting Documents * * *
Non-English original document issued by a national drug regulatory agency (original bears seal and
signature)
e.g. GMP certificate, approval letter, CPP, SmPC/PIL (Product Information) and other documents
Translator to make
declaration in presence of a
Translation to be notary public
endorsed/certified by a
responsible officer of
either the Embassy of the
Country of Origin in
Singapore OR the Notary public to be
Singapore Embassy in the authenticated by the relevant
Country of Origin authority in the Country of
Origin
b) The medicinal product should have been evaluated and approved as a non-
prescription medicine, as defined below, by at least one of the following reference
regulatory agencies:
c) The use of each active substance contained in the product should be well-
documented in the following standard reference texts:
1
Standard for the Uniform Scheduling of Drugs and Poisons
2
http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfrv5_01.html
2 DOCUMENTARY REQUIREMENTS
The documentary requirements are described in section 14 in Chapter C for NDAs and
section 22.2 in Chapter G for MAV-1s, with following additional explanatory notes:
The administrative documents required are the same as that for the abridged evaluation
route.
Product Labelling (section 1.4) for non-prescription medicines should be provided in the
form of a Patient Information Leaflet (PIL). A PIL must be clear, simple and readable so
that consumers can understand information about the product, its benefits, its risks and
how the product should be used appropriately. For details on PIL labelling requirements,
please refer to the Appendix 6 Points to consider for Singapore labelling.
The Proof of Approval (section 1.8) by the drug regulatory agency should be an official
approval letter or equivalent document that also states the forensic classification of the
product. However, HSA may still request a CPP, if deemed appropriate.
The quality requirements for an NDA non-prescription medicine are the same as that of a
POM product. MAV-1 applications do not require submission of quality documents.
If the product fulfils the criteria as defined in section 1, then the clinical data set in support
of the application may be reduced.
The clinical part of the dossier should include a Clinical Overview and supporting
information from standard reference texts as listed in section 1(c) above. The supporting
documents should be inserted in section 2.5 of Module 2 (ICH CTD) or section B of Part
IV (ACTD).
HSA reserves all rights to request for the complete clinical data set if it is deemed
appropriate.
Labelling refers to any printed or graphic information on the immediate container, outer
packaging and any other form of printed material supplied together with the product.
The product labels, PI and/or PIL must be in English. If non-English text is included in the
labelling, applicants must provide an official statement to declare that the non-English text
is complete, accurate and unbiased information and is consistent with the English text.
Information provided in the labels should be consistent with the information submitted in
the application dossier. Any deviation should be highlighted and brought to HSAs
attention.
The Outer Carton refers to the product packaging in which the immediate packaging is
placed, e.g. the carton box containing blister strips. The Inner Label refers to the label
that is fixed onto the primary container closure system, e.g. the label affixed to a bottle,
vial or ampoule. The Blister Label refers to the foil backing of a blister strip.
In addition to the legal labelling requirements, the following information shall be present
on the labelling of the product:
Outer Inner
Parameters Blister Label
Carton Label
1. Product Name
2. Dosage Form * NA
3. Name of Active Substance(s)
4. Strength of Active Substance(s)
5. Batch Number
6. Manufacturing Date * NA
7. Expiry Date
8. Route of Administration NA
9. Storage Condition * NA
Name/Logo of
Name & Address of Product Owner
10. * Manufacturer/
and/or Product Licence Holder
Product Owner
11. Name & Address of Manufacturer** * NA
12. Warnings (if applicable) * NA
13. Pack Sizes (unit/volume) NA
14. Special Labelling (if applicable) * NA
Name & Content of preservative(s) (if
15. * NA
applicable)
NA Not applicable
* Exempted for small labels such as an ampoule or vial with a nominal volume of 10 ml or less. Other
factors may be considered such as the amount of information which needs to appear on the label and the
font size necessary to achieve legibility of the information.
** The name and address of either the manufacturer or the batch releaser should be present.
If the product is supplied without an outer carton, the information that is required on the
outer carton should be stated on the inner label.
Any handwritten information on the specimens, mock-ups or text is not acceptable, with
the exception of statements such as batch number and expiry dates will be printed or
similar.
Email addresses and/or telephone numbers on the products labelling may be considered.
However, website addresses are generally not allowed unless adequately justified, for
example, in the case where the information is intended for the purpose of adverse drug
reaction reporting.
Package inserts are required for products classified as Prescription Only Medicines.
The PI is regarded as a document that contains information that will ensure safe and
effective use of the drug product. It includes a scientific, objective account of the
medicines usefulness and limitations as shown by data submitted in the application.
Information in the PI shall be non-promotional in nature.
to avoid confusion, particularly when the product is made available for self-
selection.
viii. Contraindications situations where patients should never or generally not be
treated with the medicine. In rare cases where the medicine should never be given,
this must be explicitly stated. Information on the presence of residual quantities of
potentially allergenic materials used in the manufacturing of the product should be
stated.
ix. Warnings and Precautions circumstances where caution is required to ensure
safe and efficacious use of the drug. Information on the presence of residual
quantities of potentially allergenic materials used in the manufacturing of the
product should be stated.
x. Interactions with Other Medicines and Other Forms of Interaction information on
clinically relevant interactions and other potentially serious interactions based on
the pharmacology of the medicine.
xi. Use during Pregnancy/Lactation
xii. Adverse Effects/Undesirable Effects provide an indication of severity, clinical
importance and frequency, whenever possible. Description of the adverse reaction
based on the MedDRA terminology is preferred.
xiii. Overdose and Treatment symptoms, signs and recommended treatment of
overdose or accidental poisoning.
xiv. Incompatibilities (for injections only)
xv. Storage Condition if it is included in the PI, the storage condition must be
consistent with the product label and/or outer carton.
xvi. Dosage Forms or Presentation this refers to the available dosage form(s),
formulation(s), strength(s) and/or pack size(s). The statement Not all presentations
may be available locally, or equivalent, must be stated if this section lists
unregistered presentations.
xvii. Name and Address of Manufacturer or Product Owner or Product Licence Holder
xviii. Date of Revision of Package Insert if a common PI is used for an internationally
marketed product, the date can follow the date of revision of the common PI.
However, if a Singapore-specific PI is used, the date of revision must reflect the
actual date that the local PI is revised.
Patient Information Leaflets (PILs) are required for Pharmacy Only and General Sale List
medicinal products. The PIL must be easily understood and be consistent with the
product labels and/or PI, as appropriate. The following information is required in the PIL:
i. Name of Product
ii. Description of Product
iii. What is the medicine?
iv. Strength of the medicineWhat is this medicine used for?
v. How much and how often should you use this medicine?
vi. When should you not take this medicine?
vii. Undesirable effects/side effects
viii. What other medicine or food should be avoided whilst taking this medicine?
ix. What should you do if you miss a dose?
x. How should you keep this medicine?
xi. Signs & symptoms of overdose
xii. What to do when you have taken more than the recommended dosage?
xiii. Name/logo of manufacturer/importer/product licence holder
xiv. Care that should be taken when taking this medicine?
xv. When should you consult your doctor?
If the product is sold without a PIL, the information that is required in the PIL must be
stated on the outer carton.
SEPTEMBER
SEPTEMBER
SECTION 8: DECLARATION
I am duly authorised by the applicant to make this declaration on behalf of the applicant, and enclose herewith
#
evidence of such authorisation .
I, the applicant/the authorised agent of the applicant on behalf of the applicant, declare that all information furnished
in this form is true. I am aware that a false declaration is an offence under the Medicines Act (Cap. 176). I further
undertake to notify the Health Sciences Authority of any change in the information furnished in this form.
Name: Designation:
Signature and Date: Applicants Stamp:
_______________________________
#
Please enclose appropriate evidence of authorisation. Delete this statement if applicant is a natural
person making the application personally.
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE APRIL 2011
SINGAPORE QUALITY OVERALL SUMMARY FOR CHEMICAL DRUGS
The Quality Overall Summary (QOS) should be completed to summarize the Quality (i.e.,
Chemistry, Manufacturing and Controls) portion of a New Drug Application (NDA) or a Generic Drug
Application (GDA) for a chemical drug product. Both hard copy and electronic copy of the Singapore
QOS shall be submitted for review.
The applicant is responsible for completing all sections and fields. Sections and fields that are not
applicable should be indicated with NA. An explanatory note must immediately follow all NA
entries.
INTRODUCTION
Dosage Form
Strength(s)
Route of Administration
Proposed Indication(s)
S DRUG SUBSTANCE
S 1 GENERAL INFORMATION
S 1.1 Nomenclature
Chemical Name:
Other names: (e.g. INN, BAN, USAN, common name)
S 1.2 Structure
S 2 MANUFACTURE
S 2.1 Manufacturer(s)
Name, address, and activity of each manufacturer, including contractors, and each proposed
production site or facility involved in manufacture and testing:
Site of Manufacture
[insert diagram]
S 3 CHARACTERISATION
S 3.2 Impurities
Summary of potential and actual impurities arising from the synthesis, manufacture and/or degradation:
[insert structure]
Precision
- Reproducibility
- Intermediate
- Repeatability
Precision
Limit of Quantitation
Test Name
Method Description
System Suitability
Limit of Detection
(Please specify)
(as per S4.1)
Robustness
Selectivity
Or Others
Accuracy
Linearity
Range
- Intermediate
- Repeatability
Precision
Limit of Quantitation
Test Name
Method Description
System Suitability
Limit of Detection
(Please specify)
Or Others
Accuracy
Linearity
Range
Description of the container closure system(s) for the storage of the drug substance:
S 7 STABILITY
Proposed storage conditions and re-test period (or shelf life, as appropriate):
If applicable If applicable
Testing frequency
Other
P DRUG PRODUCT
(2) Composition, i.e., list of all components of the dosage form, and their amounts on a per unit basis
(including overages, if any):
Total
(3) Composition, i.e., qualitative list of all components of proprietary materials (e.g., capsule shells,
colouring blends, imprinting inks, etc.):
P 2 PHARMACEUTICAL DEVELOPMENT
P 2.2.2 Overages
Hard Copy Location/Pages:
E-Copy Location/File Name:
Discussion of the development of the manufacturing process of the drug product (e.g., optimization of
the process, selection of the method of sterilization, etc.):
Hard Copy Location/Pages:
E-Copy Location/File Name:
Discussion of the suitability of the container closure system (described in P 7) used for the storage,
transportation (shipping), and use of the drug product (e.g., physicochemical tests, biological reactivity
tests, leaching, etc.):
Hard Copy Location/Pages:
E-Copy Location/File Name:
Discussion of microbiological attributes of the dosage form (e.g., preservative effectiveness studies):
Hard Copy Location/Pages:
E-Copy Location/File Name:
P 2.6 Compatibility
Discussion of the compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g.,
precipitation of drug substance in solution, sorption on injection vessels, etc.):
Hard Copy Location/Pages:
E-Copy Location/File Name:
P 3 MANUFACTURE
P 3.1 Manufacturer(s)
Name, address, and activity of each manufacturer, including contractors, and each proposed
production site or facility involved in manufacture and testing of product intended for Singapore:
List of all components of the dosage form to be used in the manufacturing process, and their amounts
on a per batch basis (including overages, if any):
Total
[insert diagram]
Post-Approval Commitment
Batch Size
P 4 CONTROL OF EXCIPIENTS
P 4.1 Specifications
Specifications for non-compendial excipients and for compendial excipients which include
supplementary tests not required by the monograph(s) may be found in:
Hard Copy Location/Pages:
E-Copy Location/File Name:
Justification of the specifications (e.g., evolution of tests, analytical procedures, and acceptance criteria,
exclusion of certain tests, differences from compendial standard, etc.):
Hard Copy Location/Pages:
E-Copy Location/File Name:
P 5.1 Specification(s)
- Intermediate
- Repeatability
Precision
Limit of Quantitation
Test Name
Method Description
System Suitability
Limit of Detection
(Please specify)
(as per P5.1)
Robustness
Selectivity
Or Others
Accuracy
Linearity
Range
* describe purpose of batch e.g. developmental, pilot, production, clinical, validation, commercial
Information on the characterization of impurities, not previously provided in S 3.2 (e.g., summary of
actual and potential degradation products, basis for setting the acceptance criteria, etc):
If the reference standard is a secondary standard (in house /working standard), evidence that the
secondary standard has been standardised against an official standard should be provided. Data of
studies performed on working standard against primary standard should be included, together with
appropriate Certificate of Analysis.
Hard Copy Location/Pages:
E-Copy Location/File Name:
P 8 STABILITY
In-use Storage Conditions Length of Storage prior to Start Completed In-use Test Intervals
(C, % RH, light) of In-use Stability Testing (e.g. minutes/ hours/ days)
Container Closure System Storage Conditions (with In-use Shelf Life (with In-use Period,
Storage Conditions, if applicable) if applicable)
Testing frequency
Other
Testing frequency
Other
P 9 PRODUCT INTERCHANGEABILITY
State the Product Name & strength, batch number and either BE/SIN reference product or generic
product.
Product 1: =
Product 2: =
A APPENDICES
A 3 NOVEL EXCIPIENTS
The Quality Overall Summary (QOS) should be completed to summarize the Quality (i.e.,
Chemistry, Manufacturing and Controls) portion of a New Drug Application (NDA) for a biologic
drug product. Both hard copy and electronic copy of the Singapore QOS shall be submitted for
review.
The applicant is responsible for completing all sections and fields. Sections and fields that are not
applicable should be indicated with NA. An explanatory note must accompany all NA entries.
INTRODUCTION
Dosage Form
Strength(s)
Route of Administration
Proposed Indication(s)
S DRUG SUBSTANCE
S 1 GENERAL INFORMATION
S 1.1 Nomenclature
Substance Name:
Other names:
(e.g. INN, BAN, USAN, common name)
Company or laboratory code:
S 1.2 Structure
S 2 MANUFACTURE
S 2.1 Manufacturer(s)
Name and address, of each production site or facility involved in different manufacture and testing
activities:
Activity Name and Address
[insert diagram]
S 3 CHARACTERISATION
S 3.2 Impurities
* Please indicate if it is controlled by in-process control test, product release test, or by validated purification
method.
Other materials
Name Origin / Point of Entry Control Method* & Acceptance Level
* Please indicate if it is controlled by in-process control test, product release test, or by validated purification
method.
S 4.1 Specification
Precision
- Reproducibility
- Intermediate
- Repeatability
Precision
Method Description
System Suitability
Limit of Detection
per S4.1)
(Please specify)
Quantification
Robustness
Selectivity
Or Others
Accuracy
Linearity
Limit of
Range
Description of the container closure system(s) for the storage of the drug substance:
S 7 STABILITY
Proposed storage conditions and re-test period (or shelf life, as appropriate):
If applicable If applicable
Testing frequency
Other
P DRUG PRODUCT
(1) Description of the Dosage Form (Type of container closure system used for the dosage
form and accompanying reconstitution diluent, if applicable):
(2) Composition (i.e., list of all components of the dosage form, and their amounts on a per unit
basis including overages):
Component Quality Standard Quantity per unit Function
(incl. overages)
Drug Substance
Excipients (Others)
Residuals
(note: all residual materials listed here must be stated in the PI. Refer to Appendix 6.)
Reconstitution Diluents
P 2 PHARMACEUTICAL DEVELOPMENT
P 2.2.2 Overages
Hard Copy Location/Pages:
E-Copy Location/File Name:
Batch(es) used for Final Product Comparability is the same batch used in Clinical Studies
Submitted
Yes, please provide batch number(s):
No, please provide justification
Discussion of the suitability of the container closure system (described in P 7) used for the
storage, transportation (shipping), and use of the drug product and reconstitution diluent (e.g.,
physicochemical tests, biological reactivity tests, leaching, etc.):
Hard Copy Location/Pages:
E-Copy Location/File Name:
Discussion of microbiological attributes of the dosage form where applicable (e.g., preservative
effectiveness studies):
Hard Copy Location/Pages:
E-Copy Location/File Name:
P 2.6 Compatibility
Discussion of the compatibility of the drug product with reconstitution diluent(s) or dosage
devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, etc.):
Hard Copy Location/Pages:
E-Copy Location/File Name:
P 3 MANUFACTURE
P 3.1 Manufacturer(s)
Name, address, and activity of each manufacturer, including contractors, and each proposed
production site or facility involved in manufacture and testing of product intended for Singapore:
Activity Name and Address
3.1.1 Drug Product Manufacture
Name, address, and activity of each manufacturer, including contractors, and each proposed
production site or facility involved in manufacture and testing of product intended for Singapore:
Activity Name and Address
List of all components of the dosage form to be used in the manufacturing process, and their
amounts on a per batch basis (including overages, if any):
Total
[insert diagram]
Post-Approval Commitment
Batch Size
P 4 CONTROL OF EXCIPIENTS
P 4.1 Specifications
Specifications for non-compendial excipients and for compendial excipients which include
supplementary tests not required by the monograph(s):
Hard Copy Location/Pages:
E-Copy Location/File Name:
Specifications for non-compendial excipients and for compendial excipients which include
supplementary tests not required by the monograph(s).
Hard Copy Location/Pages:
E-Copy Location/File Name:
Information regarding adventitious agents for excipients of human or animal origin (e.g.,
sources, specifications, description of the testing performed, viral safety data):
Hard Copy Location/Pages:
E-Copy Location/File Name:
P 5.1 Specification(s)
- Intermediate
- Repeatability
Precision
Limit of Quantitation
Test Name
Method Description
System Suitability
Limit of Detection
(Please specify)
(as per P5.1)
Robustness
Selectivity
Or Others
Accuracy
Linearity
Range
* describe purpose of batch e.g. developmental, pilot, production, clinical, validation, commercial
Information on the characterization of impurities, not previously provided in S 3.2 (e.g., summary
of actual and potential degradation products, basis for setting the acceptance criteria, etc):
Hard Copy Location/Pages:
E-Copy Location/File Name:
If the reference standard is a secondary standard (in house /working standard), evidence that the
secondary standard has been standardised against an official standard should be provided. Data
of studies performed on working standard against primary standard should be included, together
with a Certificate of Analysis.
Hard Copy Location/Pages:
E-Copy Location/File Name:
P 8 STABILITY
In-use Storage Conditions Length of Storage prior to Completed In-use Test Intervals
(C, % RH, light) Start of In-use Stability (e.g. minutes/ hours/ days)
Testing
Container Closure System Storage Conditions (with In-use Shelf Life (with In-use
Storage Conditions, if applicable) Period, if applicable)
Testing frequency
Other
Testing frequency
Other
A APPENDICES
A 3 NOVEL EXCIPIENTS
1 DOCUMENTARY REQUIREMENTS
Applications for human plasma-derived medicinal products will be evaluated on its quality,
safety and efficacy prior to marketing. This guideline outlines the requirements for the
Plasma Master File (PMF) and specific quality documentation to support registration of
these products.
Documents pertaining to the collection and control of source materials should be provided
as a standalone PMF. One set of the PMF and the checklist in Annex 1 of this Appendix
should be submitted together with the dossier application for registration of a human
plasma-derived product. Reference to the relevant PMF/s may be made in the following
sections of the dossier.
The plasma master file is a standalone document and it should be filed separately from
the application. When the information on plasma collection and control is available as part
of the CTD dossier, this section of the dossier should be filed as a separate standalone
document.
Once a plasma master file / a dossier section on plasma collection and control
information is received as a separate standalone document a PMF number will be
assigned to the document.
Note that for plasma collection and control information previously submitted as part of
3.2.S.2.3 section of the dossier, the following information covering the data requirements
as per the PMF Data Requirements section of this Appendix should be submitted as a
standalone document:
Plasma source and collection
Characteristics of donations
Epidemiological data on blood transmissible infections.
Selection / exclusion criteria
Plasma quality and safety
Conditions of storage and transport of plasma
A copy of the plasma specification and plasma pool batch analysis data.
1
Adapted from CPMP NfG on Plasma-derived Medicinal Products (CPMP/BWP/269/95 rev. 3) and US FDA
Guidance for Industry for the Submission of Chemistry, Manufacturing and Controls and Establishment
Description Information for Human Plasma-derived Biological Products, Animal Plasma and Serum-derived
Products
Applicants are responsible to maintain and update the PMF every two years.
The checklist in Annex 1 of this Appendix may serve as a guide to the documentary
requirements for registration of human plasma-derived medicinal products and should be
submitted with the PMF.
The data must conform to the requirements recommended by HSAs reference drug
regulatory agencies and in particular, the following documents and their subsequent
revisions:
Note for Guidance on Plasma-Derived Medicinal Products (CPMP/BWP/269/95 rev.
4);
Guideline on the Scientific Data Requirements for a Plasma Master File (PMF)
(CPMP/BWP/3794/03);
Annexes to Guideline on the Scientific Data Requirements for Plasma Master File
(PMF).
a) Documents that verify each donor of source material has undergone a proper
screening procedure and has met all established health criteria (including viral risks
requirements). The criteria used must conform to the recommendations on suitability of
blood and plasma donors set out by the US FDA, the Council of Europe and the
Australian TGA. The following details need to be provided:
i Collection centres
Names and addresses of blood/plasma collection centres, including sub-
contractors and any separate site for testing of individual donations; and,
Audits:
- Internal audits (frequency and date of last audit); and,
- Audits by regulatory authority (frequency and date of last audit).
- Confirm that centres do not collect blood/plasma from a population with a high
prevalence of infections transmitted by blood (HIV, HCV, HBV etc.);
- Confirm that there are measures taken to ensure viral safety for recipients
with respect to major pathogenic agents; and,
- Compliance with those exclusion criteria specified in appropriate documents
(Directives, Guidelines, Pharmacopoeial).
b) Documents that verify each unit of source material has been tested non-reactive for
Hepatitis B surface antigen, anti-HIV-1&2 by NAT, anti-HCV by NAT and other test
parameters as recommended by US FDA or an equivalent authority. There must be no
pooling of plasma for testing purposes. The following details need to be provided:
c) Documents that verify all steps in the processing of source material, including donor
examination, blood collection, plasmapheresis, laboratory testing, labelling, storage,
and issuing, are performed in centres that have been licensed by the US FDA or
equivalent authority for that purpose. The centres must conform to the requirements
for the collection of source materials as specified in The Collection, Fractionation,
Quality Control, And Uses of Blood and Blood Products published by the WHO. The
following details need to be provided:
d) Documents that verify all source materials are collected by aseptic techniques
designed to assure the integrity and minimise the risk of contamination of the source
material. The documents should also verify that the closure of the container used
maintains a hermetic seal. The following details need to be provided:
i. Blood bags
Information on the name of bag, manufacturer, anticoagulant solution,
composition and specification; and,
Indication on conformance to a particular standard (e.g. WHO, Ph. Eur.).
e) Documents that verify that the source materials do not contain an additive other than
citrate or acid citrate dextrose anticoagulant solution, unless it has been shown that
the processing method yields a final product free of the additive to such an extent that
the continued safety, purity, potency, and effectiveness of the final product is not
adversely affected.
1.1.2 Intermediates
Viral Inactivation:
WHO Guidelines on viral inactivation and removal procedures intended to assure
the viral safety of human blood plasma products. Technical Report Series (TRS)
No. 924, Annex 4 (Adopted by ECBS 2001)
Quality of Biotechnological Products: Viral safety Evaluation of Biotechnology
Products derived from Cell Lines of Human or Animal Origin.
The following data should be filed in various 3.2.S sections of the CTD :
a) Documents that verify all steps in the manufacture of the final product are conducted in
establishments licensed by the US FDA or equivalent authority for that purpose. All
handling and processing techniques employed should conform with current relevant
international GMP guidelines of the US FDA, the Australian TGA, the EMEA CHMP or
WHO.
b) Documents that verify each batch of source material intended for manufacture has
been tested for Hepatitis B surface antigen, antibody to HIV-1&2 and antibody to
Hepatitis C Virus by tests approved for such use by the US FDA or an equivalent
authority. Each batch of source material must also be tested for HCV RNA by genomic
amplification testing. The following details need to be provided:
i. Plasma pooling
Information on the number of individual plasma units pooled together;
List of tests performed on these plasma pools; and,
Licence number for each test kit used.
c) Documents that verify the processing method used does not affect the integrity of the
product and has been demonstrated to consistently yield a product that is safe for use
in humans. Processing methods used for the manufacture of intravenous products
should have been shown to consistently yield a product that is safe for intravenous
injection.
i. Manufacturing process
A detailed description of the manufacturing process and controls to demonstrate
proper quality control or prevention of possible contamination with adventitious
agents:
- Starting materials: Information on raw materials, intermediate products,
reagents and auxiliary materials with specifications or statements of quality of
each;
- Flowchart: A complete visual representation of the manufacturing process
flow. This flow should show the production steps, equipment, and materials
used, along with a complete list of the in-process controls and tests performed
on the product at each step. This diagram should also include information on
the methods used to transfer the product between steps;
- Detailed description: A detailed description of the fractionation, formulation,
sterilisation, purification and aseptic processes. This should include a
rationale for the chosen methods, and the precautions taken to assure
containment and prevention of contamination or cross-contamination. In-
process bioburden and endotoxin limits should be specified where
appropriate. Any reprocessing or related method should be fully validated and
described. The allowable conditions for reprocessing of all or parts of any
batch should be described; and,
- Batch record: A complete batch record of the process of production of the
biologic product should be included.
The following data should also be filed in the various 3.2.P sections of the CTD (Module 3
of ICH CTD or Part 2 of ACTD).
The physical, chemical and pharmaceutical properties of the finished product must
comply with the relevant United States, British or European Pharmacopoeial
requirements. The following details need to be provided:
a) Product testing
i. Specifications and analytical methods used for release testing and expiration
dating to assure product identity, purity, strength, or potency and lot-to-lot
consistency;
ii. Validation protocol and results for non-compendial analytical systems to
demonstrate system suitability;
iii. Lot release protocols, including specification ranges of representative lots of the
product. Specifications may include, but not limited to, biochemical purity, safety,
appearance, pH, residual moisture, excipients, endotoxins, and sterility; and,
iv. Methods and standards of acceptance, including the sampling plan and the
accuracy and precision of the analytical methods in sufficient detail to permit
duplication and verification.
c) Stability
i. Stability data for the product as packaged in the registered container closure
system;
ii. A description of the storage conditions, study protocols and results supporting the
stability of the product and any intermediates that are stored;
iii. An expiration date supported by the results of the stability study; and,
iv. When used as an excipient in medicinal products, the expiry date of the plasma-
derived product should not be earlier than that of the finished product. It is
recommended that the manufacturers have a system in place to maintain
traceability and notifications regarding post-collection information.
v. The package insert should include warning statements as per Note for Guidance
on the warning on transmissible agents in summary of product characteristics and
package leaflets for plasma derived medicinal products.
2 REGULATORY DECISION
When approved for registration, the product licence issued for a human plasma-derived
medicinal product will have the following post-approval conditions:
a) The import and sale of the product must be accompanied by a batch certification. The
batch certification and product movement records shall be maintained for 10 years
from the date of importation and be made available for inspection by HSA when
required.
b) The Product Licence Holder is responsible for ensuring that the product imported for
local sale and supply is identical, in all aspects, to that approved by HSA. The licence
holder should notify HSA of minor variations and obtain approval before
implementation as stipulated in Appendix 16 of the Guidance of Medicinal Product
Registration in Singapore.
Applicants are responsible for keeping the PMF updated. The updates are to be
submitted every two years. The biannual update does not require submission via PRISM
the update should be sent to the Generics & Biosimilar Branch of HSA with reference to
the assigned PMF number.
If a currently-registered PMF contains an update or amendment which does not affect the
properties of the drug product, but
i. the update/amendment is a significant change (e.g. significant changes to the
plasma processing), then the update should be submitted as soon as it is made
known; OR,
ii. the update/amendment is not a significant change (e.g. a change of collection
centres), then it can be submitted as part of the biannual update.
Please note that, in case of significant changes implemented before the next biannual
update, only the affected sections need to be submitted.
Appendix Yes/No
Document
Section (Encl. #)
1.1.1 Plasma Master File
1.1.1 (a) Documents that verify each donor of source material has
undergone a proper screening procedure to ensure that all
established health criteria (including viral risks requirements) are
met.
1.1.1 (a) (i) Details on collection centers
1.1.1 (a) (ii) Data on epidemiology and blood-borne infections
1.1.1 (a) (iii) Selection/ Exclusion criteria
1.1.1 (b) Documents that verify each unit of source material has been tested
non-reactive for Hepatitis B surface antigen, Anti-HIV-1 & 2 and
Anti-HCV.
1.1.1 (b) (i) Details of screening tests for markers of infection
1.1.1 (c) Documents that verify all steps in the processing of source
materials are performed in licensed centres that conform to WHOs
requirements.
1.1.1 (c) (i) Look back system to trace the path of any donation
1.1.1 (d) Documents that verify all source materials are collected by aseptic
techniques designed to assure the integrity and to minimise the
risk of contamination of the source material and that the closure of
the container used maintains a hermetic seal.
1.1.1 (d) (i) Blood bags
1.1.1 (d) (ii) Plasma quality
1.1.1 (d) (iii) Plasma specification
1.1.1 (e) Documents that verify source materials do not contain any additive
other than citrate or acid citrate dextrose anticoagulant solution
unless it has been shown that the processing method yields a final
product free of the additive to such an extent that the continued
safety, purity, potency and effectiveness of the final product is not
adversely affected.
1.1.1 (f) Documents that verify fractionator/ manufacturer and donation
centre(s)/organisation responsible for collecting plasma complies
with PIC/S GMP and procedures.
1.1.1 (g) a) Manufacturers letter of commitment.
1.2.1 Manufacturing Process and Control
1.2.1 (a) Documents that verify all steps in the manufacture of the final
product are conducted in licensed establishments for that purpose.
All handling and processing techniques employed should conform
to current relevant international GMP guidelines.
Appendix Yes/No
Document
Section (Encl. #)
1.2.1 (b) Documents that verify each batch of source material intended for
manufacture has been tested for hepatitis B surface antigen,
antibody to HIV-1 & 2, antibody to Hepatitis C Virus, and HCV
RNA.
1.2.1 (b) (i) Details of plasma pooling
1.2.1 (c) Documents that verify the processing method used does not affect
the integrity of the product and has been demonstrated to
consistently yield a product. Processing methods used for the
manufacture of products intended for IV use should have been
shown to consistently yield a product that is safe for IV injection.
1.2.1 (d) Documents that verify processing steps are conducted to minimise
risk of contamination from pyrogens, microorganisms, or other
impurities. Preservatives to inhibit growth of microorganisms are
not used of added to the product at any stage of processing.
1.2.1 (d) (i) Details of the manufacturing process
1.2.1 (d) (ii) Details of process control
1.2.1 (d) (iii) Details of assessing the risk for viral transmission
1.2.2 Drug Product
1.2.2 Statement on whether the physical, chemical and pharmaceutical
properties of the finished products comply with the relevant United
States, British or European Pharmacopoeial requirements.
1.2.2 (a) Details of product testing
1.2.2 (b) Details of container closure system/shipping containers
1.2.2 (c) Stability data
BSE is a food borne infection characterised by the presence of prion proteins, abnormal
infectious proteins in nervous tissue. The subsequent spongy degeneration of the brain
results in severe and fatal neurological signs and symptoms. There is evidence
suggesting that the new variant of human Creutzfeldt-Jakob Disease (vCJD) may be
caused by the same agent that is responsible for BSE in cattle.
The discovery of vCJD has raised concerns that the BSE agent can be transmitted to
humans. Therefore caution is warranted if biological materials from animals known to be
affected by TSE are used in the manufacture of medicinal products.
1 DOCUMENTARY REQUIREMENTS
The checklist in Annex 1 may serve as a guide to the documentary requirements, which
are further described below in sections 1.1 and 1.2. The completed checklist in Annex 1 is
to be submitted in CTD section 3.2.P.4.5 with the supporting documents submitted in ICH
CTD section 3.2.A.2 or ACTD section Q.A.2.
But for milk and certain milk derivatives, such as lactose, because these excipients are
generally considered non-infectious, a declaration from the supplier of the excipient
1
Adapted from CPMP-CVMP NfG on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy
Agents via Human and Veterinary Medicinal Products (EMEA/410/01 Rev. 2)
stating that the milk is from healthy cows fit for human consumption and no other
potentially infectious ruminant-derived materials were used in the manufacturing process
would be sufficient. This declaration is to be submitted in CTD section 3.2.P.4.5.
When manufacturers choose to use animal-derived materials, the rationale for using
these materials instead of that from the non-animal origin should be given.
The most satisfactory source of materials is from countries without any reported
case of BSE. The assessment of a countrys BSE status is based on the following:
iii. Nature of animal tissue used and measures taken to minimise BSE risk
Category A (High Infectivity): brain, spinal cord, retina, optic nerve, spinal
ganglia, trigeminal ganglia, pituitary gland and dura mater.
2
http://www.edqm.eu
3
http://www.oie.int/eng/info/en_esbmonde.htm
4
http://ec.europa.eu/food/fs/sc/ssc/outcome_en.html
a) Gelatin may be extracted from the skin and/or bones of cattle. Gelatin
extracted from skin has a lower risk than gelatin extracted from bones
especially bones from which skulls and vertebral columns have not been
carefully excluded because hide gelatin offers little opportunity for cross
contamination with potentially infective tissue (e.g. brain, spinal cord and
ganglia). Thus, it is recommended to collect bovine bones for processing
into gelatin only from BSE-free countries or from countries with a low
prevalence of BSE; it is preferable to exclude skull and vertebral columns
from bones used for gelatin. The use of bone gelatin produced by alkaline
hydrolysis (augmented, whenever possible, by additional approved
processes) rather than by acid treatment alone further reduces the risk of
contamination with TSE agents. Compliance with these precautions provides
assurance that gelatin used in the manufacture of medicinal products is
unlikely to be contaminated. Amino acids derived from gelatin are further
highly processed, so their risk may be even lower.
c) Milk and certain milk derivatives, such as lactose, are generally considered
non-infectious, regardless of geographic origin, provided that the milk is from
healthy cows fit for human consumption and no other potentially infectious
ruminant-derived materials were used in the manufacturing process.
Detailed information must be provided on the nature and quantity of each animal-
derived material used for the preparation of:
Drug substance;
Excipients and adjuvants;
Raw and starting materials and reagents used in production e.g. bovine
serum albumin, enzymes and culture media including those used to prepare
working cell banks or new master cell banks.
Materials that come into direct contact with the equipment used in the manufacture
of the medicinal product or that come in contact with the medicinal product and
therefore have the potential for contamination should also comply with these
guidelines. Likewise, materials used in the qualification of plant and equipment,
such as culture media used in media fill experiments to validate the aseptic filling
process shall be considered in compliance with these guidelines.
The use of animal-derived materials that have NOT been awarded Certificates of
Suitability by the European Directorate for the Quality of Medicines & Healthcare (EDQM)
may still be acceptable, subjected to the risk assessment of the TSE in the form of a
detailed assessment report.
i. The scope of this report should include section 1.1 (b) as well as the risk factors
associated with the route of administration and the maximum therapeutic dosage
(daily dosage and duration of treatment) of the product.
If claims are made that inactivation of TSE agents occurs during the manufacturing
process, then relevant information on the process should be submitted for
evaluation.
The Product Licence holder is responsible for ensuring that the product imported for local
sale and supply is identical, in all aspects, to that approved by the licensing authority. The
licence holder should notify HSA of variations and obtain approval before implementing
the variation if necessary (for example, change of source materials for manufacturing).
3 CONCLUSION
The above guidelines only serve as guidance. Pharmaceutical manufacturers and owners
are required to observe international best practices at all times and to comply with the
requirements of the EMEA, USA, Australia, Canada, in particular, the requirements set
down in the given references and their subsequent revisions.
4 REFERENCES
a) CPMP & CVMPs Note for Guidance on Minimising the Risk of Transmitting Animal
Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products,
EMEA/410/01 Rev. 2 October 2003).
b) Guidance for Industry The Sourcing and Processing of Gelatin to Reduce the
Potential Risk Posed by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated
Products for Human Use, by US FDA.
c) Ph. Eur. general monograph on Product with risk of transmitting agents of animal
spongiform encephalopathies.
g) Terrestrial Animal Health Code, World Organisation for Animal Health (OIE).
h) Use of Materials Derived from Cattle in Medical Products Intended for Use in Humans
and Drugs Intended for Use in Ruminants; Proposed Rule by FDAs Department of
Health and Human Services.
i) TGA Supplementary requirements for Therapeutic Goods for Minimising the Risk of
Transmitting Spongiform Encephalopathies (TSEs).
k) Guidance for Industry Revised Preventive Measures to Reduce the Possible Risk of
Transmission of CreutzfeldtJakob Disease (CJD) and Variant Creutzfeldt-Jacob
Disease (vCJD) by Blood and Blood Products. U.S. FDA, Department of Health and
Human Services, Center for Biologics Evaluation adn Research, May 2010.
1.1 (b) (iii) Declaration of the nature of the animal tissue used.
1.1 (b) (iv) Nature and quantity of each animal-derived material used:
As a drug substance.
As an excipient or adjuvant.
1.1 (b) (iii) Declaration of the nature of the animal tissue used.
1.2 (a) Details of the risk factors associated with the route of
administration and maximum therapeutic dosage of the
product.
1.1 (b) (iv) Nature and quantity of each animal-derived material used:
As a drug substance.
As an excipient or adjuvant.
1.2 (a) (ii) Relevant information to support the claim that the
manufacturing process is capable of inactivating TSE agents.
Applicants are advised to be familiar with The ASEAN Guideline on the Conduct of
Bioavailability and Bioequivalence Studies1 on the conduct of bioavailability (BA) and
bioequivalence (BE) studies for the purposes of drug registration. Applicants are also
advised to consult the relevant international guidelines from EMA CHMP2, US FDA3 or
WHO for the conduct and analysis of bioavailability and bioequivalence studies.
From 1st April 2004, in vivo BE data is required for Prescription Only Medicines (POM) in
oral solid dosage forms. Also, GDA-2 applications will 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 was submitted to HSA before 1 April 2004.
HSA reserves the right to request for any additional information required to determine the
product interchangeability of the generic product to the Singapore reference product.
1 PRODUCT INTERCHANGEABILITY
For generic products containing a different salt or ester form of the active substance
compared 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 reference
product.
2 BE STUDY
The report of a BE study should include the complete documentation of its protocol,
conduct and evaluation in compliance with GCP and related ICH E34 guideline.
Deviations, additions, or omissions from existing guidelines must be explained, either by
introductory remarks or within each relevant module/part of the submission, whichever is
more appropriate. Examples of information to be included in the report are:
1
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
2
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000043.jsp
&murl=menus/regulations/regulations.jsp&mid=WC0b01ac05800240cb&jsenabled=true
3
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm121568.htm
4
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000429.jsp
&murl=menus/regulations/regulations.jsp&mid=WC0b01ac0580029590
The generic or test product used in the BE study must be the same as the Singapore
drug product submitted for registration. In other words, the test product must be
manufactured at the same drug substance and drug product manufacturing sites by the
same manufacturing processes as submitted in the GDA registration dossier. The test
product used in the BE study should also be from a batch of at least 100,000 units or 1/10
of production scale, whichever is greater.
It is highly recommended that the reference product used in the BE study be the same as
the Singapore reference product i.e. the BE reference product should be of the same
strength as the generic product and manufactured from the Singapore registered drug
product manufacturing site. Details of the manufacturing source of the Singapore
reference product can be found by searching HSAs online database5.
a) The reference product is registered in, and obtained from, a country with a competent
regulatory system as defined by WHO;
b) It is documented that the reference product is marketed in the country of origin
i. by the same innovator company or corporate entity that markets the same drug
product (same dosage form and strength) in Singapore; or,
ii. through a licensing arrangement with the innovator company or corporate entity that
markets the same product in Singapore;
c) The reference product is a conventional, immediate-release oral dosage form (tablet,
capsule) or an enteric coated tablet or capsule formulation that releases the drug
substance promptly once the enteric coating has dissolved;
d) The ingredients in the BE reference product are qualitatively identical to those used in
the Singapore reference product, with exception of minor excipients that are unlikely
to affect the bioavailability of the product (e.g. colourants and inks);
e) The active ingredient has a well-described dose response curve and does not exhibit
the following:
i. a narrow therapeutic range or safety margin e.g. does not require careful dosage
titration or patient monitoring;
ii. a steep dose-response relationship;
iii. a risk of serious undesired effects; and/or,
5
http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=load
Applicants should ensure that the submitted BE study is complete, including all
appendices and data, as per the relevant guidelines.
3 COMPARATIVE DISSOLUTION
A dissolution test is used as a tool to identify formulation factors that may influence and
have a critical effect on the BA of the product. A dissolution test is also used in the quality
control to ensure batch-to-batch consistency of production batches and dissolution
profiles of production batches remain similar to the pivotal clinical trial batch(es).
Dissolution profiles should be determined in at least three dissolution media within the
physiological range (pH 1 to 7.5), such as 0.1 N HCl, a pH 4.5 buffer and a pH 6.8 buffer.
One of the dissolution media should be described in the BP or USP monograph, if one
exists.
For comparative in vitro dissolution studies, the following data should be submitted:
a) individual dissolution data in each of the media;
b) mean, range and RSD values of 12 units conducted in the three different media; and,
c) statistical comparison using a procedure described in relevant international guidelines
e.g. F2 calculations.
The results of in vitro dissolution tests obtained from the test and reference products used
in the BE study should be reported.
For more information on the conduct and reporting of comparative dissolution studies,
applicants are advised to refer to the ASEAN Guideline on the Conduct of Bioavailability
and Bioequivalence Studies and other relevant international guidelines, as appropriate.
4 BIOWAIVER REQUEST
In general, BE data or a justification for not providing such data are not required for the
following:
a) Simple or complex solutions that do not contain any ingredient which can be regarded
as a pharmacologically active substance;
b) Haemodialysis and peritoneal dialysis solutions;
c) Simple aqueous solutions intended for intravenous injection or infusion containing the
same active substance(s) in the same concentration as currently registered products.
Simple solutions do not include complex solutions such as micellar or liposomal
solutions;
d) Solutions for injection that contain the same active ingredients and excipients in the
same concentrations as currently registered products and which are administered by
the same route(s);
e) Products that are powder for reconstitution as a solution and the solution meets either
criterion (c) or (d) above;
f) Oral immediate-release tablets, capsules and suspensions containing drug
substances with high solubility and high permeability and where the drug product has
a high dissolution rate, provided that the applicant submits an acceptable justification
for not submitting BE data in terms of the CHMP or FDA guidelines;
g) Oral solutions containing the same active ingredient(s) in the same concentration as a
currently registered oral solution and not containing excipients that may significantly
affect gastric passage or absorption of the active ingredient(s);
h) Products for topical use provided that the product is intended to act without systemic
absorption when applied locally;
i) Products containing substances which are not systemically or locally absorbed and do
not contribute to a therapeutic effect (e.g. barium sulphate enemas, powders in which
no ingredient is absorbed). If there is doubt as to whether absorption occurs, a study
or justification may be required;
j) Otic or ophthalmic products prepared as aqueous solutions and containing the same
drug substance(s) in the same concentration; and,
If the justification is not considered adequate, the applicant will be required to provide
relevant biopharmaceutic data.
This document reflects the current thinking of HSA on the minimum data necessary for
assessment. HSA reserves the right to request additional information if deemed
appropriate.
Generic Product used in BE study Reference product used in BE study Reference Product used in BE study
Manufacturing Site Manufacturing Site Strength
Manufacturing site Generic Product used in BE Manufacturing site Reference Product in BE Strength of Reference Product used in BE
same as proposed site for Singapore GDA same as registered Singapore site same as registered Singapore strength
from different manufacturing site from different manufacturing site is not available in Singapore
(not acceptable, test product used in BE study
One RED tick box: BE study acceptable with bridging data (comparative dissolution)
must be from same manufacturing site as the
proposed Singapore product) More than one RED tick box BE study not acceptable; considered two steps
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 12A - Page 1 of 1
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE APRIL 2011
Registration of Indian generic products may be possible through the CECA scheme
provided that the application meets the eligibility and documentary requirements. This
document is intended to provide assistance in the submission of applications under the
CECA scheme.
1 ELIGIBILITY CRITERIA
For eligibility of registration under the CECA scheme, the following criteria must be
satisfied:
Applicants should note that approval by these reference regulatory agencies does not
obligate HSA to approve the application.
1
Note for Guidance on the Investigation of Bioavailability and Bioequivalence. CPMP/EWP/QWP/1401/98.
d) Products that have been rejected, withdrawn from, approved via appeal process or
pending deferral by a national drug regulatory authority; and,
e) Products that have been approved by one of the reference agencies via an
accelerated/fast-track approval, approval under exceptional circumstances or an
equivalent approval process.
2 REGISTRATION PROCESS
Applications for registration of Indian generic products shall undergo the same process as
other medicinal products as described in the Guidance of Medicinal Product Registration
in Singapore (hereinafter referred to as Guidance). Figure 3 on page 12 of the Guidance
is a flowchart of the registration process.
It is highly recommended for applicants wishing to submit applications under the CECA
scheme to undergo a pre-submission consultation. This consultation is to determine the
eligibility of the dossier and suitability of the dataset for registration under this scheme. In
turn, this should facilitate the registration process as it may help to minimize/reduce
potential delays i.e. the need for Input Requests in the registration process.
Dossiers submitted under the CECA scheme must be in the ICH CTD or ACTD format.
Dossiers submitted should also be in electronic format, either as a CD/DVD or uploaded
into PRISM. See section 6.3.1 in the Guidance for more information.
Administrative documents must be submitted in both hard copy and soft copy. All official
documents must be original or certified true copies.
The administrative documentary requirements for the CECA scheme are similar to the
GDA verification evaluation route. See section 17.1 in the Guidance for more information
on the specific administrative document required. However, applicants should note that
the requirements listed in table below are specific to the CECA scheme:
1.11 GMP certification Valid GMP certificate and latest inspection report as
issued by the reference agency.
1.14 Declaration Declaration letter stating that the Singapore product to
be registered and the information submitted are exactly
the same as those submitted to the reference agency.
#
if the drug substance section is submitted to the primary reference agency as a Drug Master File, the
complete assessment report of the DMF, including assessment on the Question & Answer documents
between the DMF Holder & Agency and all annexes should be provided. Assessment reports, approval
letters and/or documents pertaining to post-approval DMF updates should also be submitted, if
applicable.
The assessment reports must be unredacted or unedited. Reports obtained from the
public domain are deemed unacceptable.
Applicants should note that, with effect from 1st April 2004, all overseas drug product
manufacturing sites previously not registered with HSA will be subjected to a GMP
Conformity Assessment by HSA. Refer to GUIDE-202 on the HSA website for more
information.
The documentary requirements for the CECA scheme is the same as the GDA abridged
evaluation route, which includes the Singapore Quality Overall Summary and Quality
Overall Summary.
The CMC quality documents required for the CECA scheme is as follow:
2
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/guidelines.html
reference agency and sponsor and the approval letter for the DMF update from the
reference agency.
Applicants should refer to section 17.5.2 of the Guidance for more detailed information.
Data submitted to HSA must be the same as the data package submitted to the reference
regulatory agencies. Differences between the dossier submitted to HSA and data
reviewed by the reference regulatory agencies will not only delay the processing of the
application, but may also lead to re-routing of the dossier to the abridged evaluation route
if significant undisclosed differences have been discovered.
Non-clinical documents (ICH CTD Module 4 or ACTD Part 3) are not required.
The clinical documents (ICH CTD Module 5 or ACTD Part 4) required for the CECA
scheme is as follow:
i. All clinical documents submitted to the reference agency that had approved the
generic product. Examples of clinical documents include bioequivalence (BE)
studies, justification for biowaiver of BE studies and other relevant documents; and,
ii. All Questions and Answers between the reference agency and Sponsor during the
evaluation which led to market authorization of the generic product the Answers
should include all supporting documents in response to the Questions.
Applicants are to note that generic products applied through the CECA scheme must also
demonstrate product interchangeability to the Singapore reference product. As such,
applicants should refer to Appendix 12 of the Guidance for more information.
A regulatory decision is made based on the evaluation of the submitted data package.
Applicants should refer to section 9 of the Guidance for more information.
Upon issuance of a Product Licence, applicants are responsible fulfilling all post-approval
licensing conditions attached to the Licence. Applicants should view the licensing
conditions online for specific details.
2.3 Timeline
Because this scheme was established to facilitate market entry of Indian generic
products, the table below describes the target processing timeline, in working days and
excluding any stop-clocks:
NOTE: the screening timeline begins from the date of submission of the complete dossier.
Applicants are advised to refer to Appendix 1 of the Guidance for more information. As
such, HSA reserves the right to amend the application date when all documents have been
submitted.
2.4 Fees
The screening fee is payable at the time of PRISM submission. The evaluation fee is
payable upon acceptance of the dossier for evaluation. The screening and evaluation
fees are non-refundable, regardless of the final decision by HSA. Thus, applicants are
advised to ensure that the dossier is compiled according to the required format and
complete prior to submission.
The progressive payment scheme was implemented for applications under this route to
allow payment of evaluation fees by instalments. The evaluation fees of the CECA
scheme can be paid by instalments via the progressive payment scheme.
Please be reminded that every section in this form MUST be filled up in order to facilitate the
process.
Additional comments/information:
Difficulty of the inquiry? Easy - applicant kindly reminded to review guidance documents
Medium
Hard - proposed guidance update(s): section ____________
Recommended Course of Action for the Applicant: (Check all that apply)
Include a copy of this form in the submission, attach any relevant correspondence
Submit as a MIV-2 application
Submit as a MIV-1 application
Submit documents/sections as proposed
Submit the following documents/sections in support of the proposed changes
HSA reserves the right to re-route the application type, split unrelated changes or request for
additional information during the course of the screening/evaluation.
TABLE OF CONTENTS
PART A: INTRODUCTION
With effect from 1 July 2011, MIV-1 changes should be grouped together as one
application when these changes are consequential changes. A consequential change is
regarded as a change that is unavoidable and is a direct result of another change, not
simply a change that occurs at the same time. HSA reserves the right to split any MIV-1
application with non-consequential changes into separate MIV applications.
HSA also reserves the right to re-categorise the MIV if deemed appropriate.
NOTE: Product licence holders are encouraged to email the MIV Filing and
Submission Inquiry Form in Appendix 14 for any issues regarding MIV filing, such
as the absence of a relevant checklist for a particular change.
1 REGISTRATION PROCESS
An MIV is submitted via the Amendment to a Licence of Western Drug Product form in
PRISM.
Product licence holders should disclose all proposed changes in Section 0 Licence
Summary under Section 0.4 Amendment Summary, and in the Table of Amendment
Details, which can be downloaded via the link indicated in Section 0.5 Amendment
Details. Any undisclosed variation(s) embedded in the submitted data, or any follow-on
changes not specifically requested by HSA, will not be considered for evaluation.
2 DOCUMENTARY REQUIREMENTS
The following documents must be submitted with each MIV submission, as given in Table
A below:
The checklists for MIV-1 and MIV-2 applications for chemical drug products are located in
Part B and C of this Appendix. These checklists will serve as a guide for submitting the
required documents relevant to each proposed MIV. When submitting the Checklist, the
following should be included:
A copy of the relevant checklist(s) to each proposed MIV(s) the boxes should be
checked to ensure that the required documents are included in the submission; and,
The Declaration for the MIV with the submission date and the product licence
holders name and signature.
The Table of Amendment Details should concisely describe the proposed MIV(s). The
following information must be stated in the Table:
Section(s) of the original dossier affected by the change(s);
Current and proposed condition(s);
Reason(s) for the change(s); and,
Registration status and date of the proposed change(s) in other countries/agencies
that had approved the variation(s), especially the country of origin and HSAs
reference agencies.
For an MIV application with multiple related or unrelated variations, all of the
supporting documents for each individual variation should be submitted. If the
required documents have not been submitted, justification must be provided.
NOTE: For unstable drug substances or critical dosage forms, whenever stability
data is required, a minimum of three batches (at least two pilot scale or larger) must
be submitted.
This document reflects the current thinking of HSA on the minimum data necessary for
assessment. Product licence holders are responsible for ensuring that all necessary
validations were conducted to demonstrate that the change does not adversely affect the
quality, safety or efficacy of the product concerned. HSA reserves the right to request for
additional information if deemed appropriate.
Product licence holders should be familiar with the documentary requirements for MIV
submissions to facilitate the review process.
The following documents must be submitted with each MIV submission, as given in Table
A below:
When submitting the Checklist for Minor Variation Applications (MIV-1) for Chemical
Drugs, product licence holders must make the following declaration:
There are no other changes than those identified in Section 0.4 Amendment
Summary;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
NOTE: When submitting the Checklist, please delete the MIV-1 checklist
category(ies) that do not relate to the MIV application being submitted.
There are no other changes than those identified in Section 0.4 Amendment
Summary;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
4) Comparative batch analysis data (in a table) of at least two batches (minimum
pilot scale) of the drug substance manufactured according to both the currently
approved and proposed processes;
5) If retest period is not stated on the CEP, results of real time and accelerated
stability data of at least 6 months on two pilot batches of the drug substance
manufactured according to the proposed process in accordance with the
relevant guidelines should be provided;
6) A letter of commitment to conduct real time stability study for the drug product
manufactured with the drug substance from the new manufacturing process,
and report to HSA of any out-of-specification result (with proposed action) or
when requested.
Supporting Documents
1) Risk assessment: prior knowledge, consistency of performance of sterilizer,
historical batch analysis data, risk of loading pattern/container/contamination
from the environment to product sterility, re-processing plan and etc.
2) Process validation of sterilizer: type/design/cycle parameter, container closure
system integrity, heat distribution study for 3 consecutive runs, heat penetration
studies for 3 consecutive runs for each loading pattern and container size,
effectiveness of the load monitor used for each routine run, bioburden, sterility
assurance level of 10-6 or better should be demonstrated, re-processing (if
applicable) and etc.
3) Control Strategy: Tabulation of all validated critical process parameter and
loading pattern, describes the process and requirement for releasing/rejection
of a batch, bioburden monitoring and control program, segregation of sterile
from non-sterile product, routine maintenance/re-validation program for
sterilizer and etc.
4) Approval letter for parametric release from regulatory agency of any PIC/s or
Japan
5) Revision of the certificates of analysis that parametric release is now the
method used to provide assurance of the requirement of sterility
If a proposed MIV-2 does not meet its specified conditions, then the MIV must be
submitted as an MIV-1 with supporting documents. HSA reserves the right to re-
categorise the MIV if deemed appropriate.
Product licence holders should be familiar with the documentary requirements for MIV
submissions to facilitate the review process.
The following documents must be submitted with each MIV submission, as given in Table
A below:
When submitting the Checklist for Minor Variation Applications (MIV-2) for Chemical
Drugs, product licence holders must make the following declaration:
There are no other changes than those identified in Section 0.4 Amendment
Summary;
The change(s) will not adversely affect the quality, efficacy and safety of the
product;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
NOTE: When submitting the Checklist, please delete the MIV-2 checklist
category(ies) that do not relate to the MIV application being submitted.
There are no other changes than those identified in Section 0.4 Amendment
Summary;
The change(s) will not adversely affect the quality, efficacy and safety of the
product;
All Conditions for the notification(s) concerned are fulfilled; and,
The required documents for the notification(s) have been submitted.
(a) the stability studies on at least two batches of drug substance (pilot or
production scale) have been started and will continue to the registered re-test
period/shelf-life; AND,
(b) to provide the data to HSA if there are any out-of-specification results (with
proposed action) or when requested.
9) A declaration that
(a) the stability studies on at least two batches (pilot or production scale) of
drug product have been started and will continue to the registered shelf-life;
AND,
(b) to provide the data to HSA if there are any out-of-specification results (with
proposed action) or when requested.
10) A bioequivalence study or justification for biowaiver;
11) Comparative dissolution data between the current formulation (production
scale) and the proposed formulation (at least pilot scale) in accordance with the
relevant guidelines.
C28 Tightening of Release and Shelf Life Specifications or Addition of New Test
Parameter and Limit of Drug Product
Conditions
- The new test method does not concern a novel non-standard technique or a standard
technique used in a novel way
Supporting Documents
1) A comparative table of the current and revised release and shelf life
specifications of the drug product with the changes clearly indicated (e.g.
underscored, highlighted);
2) Revised release and shelf life specifications of the drug product;
3) Batch analysis of the drug product for all tests in the new specification;
4) Descriptions of any new analytical method and a summary of validation data,
if applicable.
C33 Addition or Replacement of Measuring Device for Oral Liquid and Other
Dosage Forms
Conditions
- The size and the accuracy of the proposed measuring device (if applicable) must be
compatible with the approved posology stated in the currently-registered PI
- The new device is compatible with the drug product
Supporting Documents
1) Detailed description and drawing of the device;
2) The composition of the device material;
3) Scientific justification and evidence that shows that size and accuracy of the
device are adequate for the approved posology stated in the product
labelling.
TABLE OF CONTENTS
PART A: INTRODUCTION
This document describes the requirements of a Minor Variation Application (MIV) submitted
for an existing registered biologic drug product in Singapore. Product licence holders
should be familiar with the contents of this document, the Guidance on Medicinal Product
Registration in Singapore and the governing legislation prior to submitting an MIV to HSA.
With effect from 1 July 2011, MIV-1 changes should be grouped together as one
application when these changes are consequential changes. A consequential change is
regarded as a change that is unavoidable and is a direct result of another change, not
simply a change that occurs at the same time. HSA reserves the right to split any MIV-1
application with non-consequential changes into separate MIV applications.
HSA also reserves the right to re-categorise the MIV if deemed appropriate.
NOTE: Product licence holders are encouraged to email the MIV Filing and
Submission Inquiry Form in Appendix 14 for any issues regarding MIV filing, such as
relevant checklist could not be found.
1 REGISTRATION PROCESS
Product licence holders should disclose all proposed change(s) in Section 0 Licence
Summary under Section 0.4 Amendment Summary and in the Table of Amendment
Details, which can be downloaded via the link indicated in Section 0.5 Amendment Details.
Any undisclosed variation(s) embedded in the submitted data, or any flow-on changes not
specifically requested by HSA, will not be considered for evaluation.
2 DOCUMENTARY REQUIREMENTS
The following documents must be submitted with each MIV submission, as given in Table A
below:
The Checklist for Minor Variation Applications for Biologic Drugs is located in Part B, C and
D of this guidance document. These checklist serves as a guide for submitting the required
documents relevant to each proposed MIV. When submitting the Checklist, the following
should be included:
A copy of the relevant checklist(s) to each proposed MIV(s) the boxes should be
checked to ensure that the required documents are included in the submission; and,
The Declaration for the MIV with the submission date and the local product licence
holders name and signature.
The Table of Amendment Details concisely describes the proposed MIV(s). The following
information must be stated in the Table:
Section of the original dossier affected by the change(s);
Current and proposed condition(s);
Reason for the change(s); and,
For an MIV application with multiple related or unrelated variations, all of the
supporting documents for each individual variation should be submitted. If the
required documents have not been submitted, justification must be provided.
This document reflects the current thinking of HSA on the minimum data necessary for
assessment. Product licence holders are responsible for ensuring that all necessary
validations were conducted to demonstrate that the change does not adversely affect the
quality, safety or efficacy of the product concerned. HSA reserves the right to request
additional information if deemed appropriate.
Product licence holders should be familiar with the documentary requirements for MIV
submissions to facilitate the review process.
The following documents must be submitted with each MIV submission, as given in Table
A below:
When submitting the Checklist for Minor Variation Applications (MIV-1) for Biologics,
product licence holders must make the following declaration:
There are no other changes than those identified in Section 0.4 Amendment
Summary;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
NOTE: When submitting the Checklist, please delete the MIV-1 checklist
category(ies) that do not relate to the MIV application being submitted.
There are no other changes than those identified in Section 0.4 Amendment
Summary;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
B5 Change of Excipient
For any change of the qualitative or quantitative formulation of the excipients of drug
substance and/or drug product.
HSA reserves the right to re-categorise the application to NDA, if deemed appropriate.
Supporting Documents
1) A table of the current and revised product formulation with the changes
clearly indicated (e.g. underscored, highlighted) and the calculated
percentage of changes;
2) Revised product formulation;
B6 Change of Specifications
For any change of release and/or shelf life specifications of drug substance, drug
product, in-process tests, product release tests, and/or stability tests
Supporting Documents
1) Scientific and/or historical data with justification to support the change;
2) Currently registered version of the release and/or shelf life specifications with
the proposed change(s) clearly highlighted, underscored, or otherwise
indicated;
3) Proposed release and/or shelf life specification;
4) Batch analysis for all tests in the proposed specification;
5) For any change of the stabilityindicating parameters in the specification,
(a) results of appropriate stability studies of at least three production batches
tested according to the proposed specification in accordance with the relevant
stability guidelines; AND,
(b) a letter of undertaking to continue the stability studies to the retest period
or shelf life, where applicable, and to report to HSA of any out-of-specification
result (with proposed action) or when requested.
If a proposed MIV-2 does not meet its specified conditions, then the MIV must be
submitted as an MIV-1 with supporting documents. HSA reserves the right to re-
categorise the MIV if deemed appropriate.
Product licence holder should be familiar with the documentary requirements for MIV
submissions to facilitate the review process.
The following documents must be submitted with each MIV submission, as given in Table
A below:
When submitting the Checklist for Minor Variation Applications (MIV-2) for Biologics,
product licence holders must make the following declaration:
There are no other changes than those identified in Section 0.4 Amendment
Summary;
The change(s) will not adversely affect the quality, efficacy and safety of the
product;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
NOTE: When submitting the Checklist, please delete the MIV-2 checklist
category(ies) that do not relate to the MIV application being submitted.
There are no other changes than those identified in Section 0.4 Amendment
Summary;
The change(s) will not adversely affect the quality, efficacy and safety of the
product;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
Variations submitted for Plasma Master Files are categorized as a MIV-1 application.
Product licence holders should be familiar with the documentary requirements for MIV
submissions to facilitate the review process.
The following documents must be submitted with each MIV submission, as given in Table
A below:
When submitting the Checklist for Minor Variation Applications (MIV-1) for Biologics,
product licence holders must make the following declaration:
There are no other changes than those identified in Section 0.4 Amendment
Summary;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
There are no other changes than those identified in Section 0.4 Amendment
Summary;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
TABLE OF CONTENTS
1 INTRODUCTION ............................................................................................................. 3
1.1 Scope.................................................................................................................. 3
2 BASIC PRINCIPLES....................................................................................................... 4
1 INTRODUCTION
Biological medicines are produced using a living system or organism. They are different from
traditional chemical medicines in many ways. The manufacturing process of a biological
medicine is highly complex and is a determining factor in the development of a biological
medicine. The definition of process includes the type or identity of the source material and
the individual process steps in cell fermentation, protein purification, sterile filling and drug
product formulation. Even very small process changes can result in significant differences in
the clinical properties of the biological medicines.
The expiration of the patents on many biological products has prompted the development of
these products as similar biological products. A similar biological product would have an
abbreviated non-clinical and clinical development programme leveraging on the existing
information of the original product and focusing on demonstration of similarity with the
original product. While the launch of such similar biological products would provide patients
with potentially cheaper alternatives, it is also prudent to ensure that the quality, safety and
efficacy of such products are not compromised.
1.1 SCOPE
This guidance document describes the basic principles of a similar biological product, as well
as the procedures and requirements for registration of a similar biological product.
Applicants are expected to comply with the procedures and requirements laid out in this
guidance. However, alternative approaches to the specified procedures and requirements
may be accepted, provided there is adequate scientific evidence and justification. Any
alternative approach should be discussed with HSA and agreed upon in advance in order to
avoid rejection of the application. Conversely, HSA may request for information or specify
conditions not described in this document but deemed necessary to adequately assess the
safety, efficacy and quality of the product under evaluation.
1.2 PURPOSE
This guidance document is adapted mainly from the EMEA guidelines on similar biological
products1,2, with consideration of Singapores local regulatory environment.
1.3 DEFINITION
1
http://www.emea.europa.eu/htms/human/humanguidelines/multidiscipline.htm
2
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.jsp&murl=me
nus/regulations/regulations.jsp&mid=WC0b01ac058002956b
applicant, and is subject to all applicable data protection periods and/or intellectual property
rights for the original product.
Applicants are advised to refer to sections 11 & 12 in the Guidance on Medicinal Product
Registration in Singapore3 for details on Data Protection, Data Exclusivity and Patent
Linkage.
2 BASIC PRINCIPLES
2.1 BIOSIMILAR PRODUCT APPROACH
Biological medicinal products are usually more difficult to characterise than chemically
derived medicinal products. In addition, there is a spectrum of molecular complexity among
the various products (recombinant DNA, blood or plasma-derived, immunologicals, gene and
cell-therapy, etc.). Moreover, parameters such as the three-dimensional structure, the
amount of acido-basic variants or post-translational modifications such as the glycosylation
profile can be significantly altered by changes, which may initially be considered to be minor
in the manufacturing process. Thus, the safety/efficacy profile of these products is highly
dependent on the robustness and the monitoring of quality aspects.
Current technologies, such as peptide mapping, protein sequencing, and mass spectroscopy
enable manufacturers to determine, with certainty, the amino acid sequence of a
recombinant protein. However, the amino acid sequence is the most rudimentary
characteristic of a protein. Conclusive analysis of other aspects of a protein's structure
requires much more sophisticated technologies and is fraught with uncertainties that are
proportional to the size and complexity of the protein itself. Therefore, the ability to predict
the clinical comparability of two products depends on our understanding of the relationship
between the structural characteristics of the protein and its function, as well as on our ability
to demonstrate structural similarity between the biosimilar product and the reference
product. Although this may be currently possible for some relatively simple protein products,
technology is not yet sufficiently advanced to allow this type of comparison for more complex
protein products. Similarity will therefore need to be confirmed via non-clinical and clinical
studies.
The biosimilar product approach is more difficult to apply to other types of biological
medicinal products, which by their nature are more difficult to characterise, or which have
little clinical and regulatory experience in their evaluation. Whether a medicinal product
3
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
would be acceptable using the biosimilar product approach depends on the state of the art of
analytical procedures, the manufacturing processes employed, as well as clinical and
regulatory experience.
Vaccines, blood or plasma-derived products & their recombinant alternatives, and other
types of biological medicinal products, such as gene or cell products used for advanced
therapy, and human tissues or cells intended for human application, are of a complex nature
and applications for biosimilar products for such products will not be considered at the
present moment.
Products employing clearly different approaches to manufacture than the reference product
(e.g., use of transgenic organisms versus cell culture, or use of eukaryotic versus prokaryotic
host cell), or any use of a non-analogous host cell line or change to the culture conditions
(e.g. cell monolayer versus suspension), would require a strong rationale in order to be
considered eligible as a biosimilar product.
The same chosen reference product should be used throughout the comparability
assessment for quality, safety and efficacy studies during the development of a biosimilar
product in order to allow the generation of coherent data and conclusions. The chosen
reference product used should be of the corresponding strength and from the Singapore
registered drug product manufacturing source.
The active substance of a similar biological medicinal product must be similar, in molecular
and biological terms, to the active substance of the reference medicinal product.
The pharmaceutical form, strength, and route of administration of the similar biological
medicinal product should be the same as that of the reference medicinal product. When the
pharmaceutical form, the strength or the route of administration is not the same, additional
data in the context of the comparability exercise should be provided. Any differences
between the similar biological medicinal product and the reference medicinal product will
have to be justified by appropriate studies on a case-by-case basis.
3 SUBMISSION PROCEDURE
Applicants are encouraged to discuss the submission and documentary requirements in a
pre-submission consultation prior to submission of a biosimilar product. The request for a
consultation should be made in writing, with the purpose and agenda for the consult stated,
via email to HSA_MedProd_Registration@hsa.gov.sg.
Application for a biosimilar product is to be submitted as a new drug application (NDA) via
the abridged dossier evaluation route. The timelines and fees applicable for a NDA via the
abridged evaluation route apply. The administrative requirements are as per required for a
NDA via the abridged dossier evaluation route.
The biosimilar product is to be evaluated and approved by at least one of HSAs reference
agencies namely, Australia TGA, Health Canada, EMEA and US FDA. If not, the submission
is to be submitted with the complete dataset as per required for a new biological product.
Application for a biosimilar product would not qualify for evaluation via the verification
evaluation route as with all biological products.
4 DOCUMENTARY REQUIREMENTS
4.1 QUALITY DOCUMENTATION
The quality documentation requirements are adapted from the CHMP Guideline on Similar
Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active
Substance: Quality Issues (CHMP/49348/05)5, and CHMP Guideline on Comparability of
Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality
Issues (CHMP/BWP/3207/00 Rev. 1)6.
The complete quality dossier as required for a new biological product submitted via the
abridged dossier evaluation route is to be submitted, including the Singapore Quality Overall
Summary (QOS).
The biosimilar product shall, with regards to the quality data, fulfill all technical content
requirements for Module 3 of the ICH CTD or Part 2 of the ACTD, and satisfy the technical
requirements of the monographs of pharmacopoeia and any additional requirements, such
as defined by HSA and ICH guidelines. Complete information on the development,
manufacture and control of both the active drug substance and the drug product should be
provided.
Comparability data between the biosimilar product and the reference product (in terms of
quality) must be submitted in the quality dossier. The extent of the comparability studies and
the assessment criteria depends on the complexity of the product and the capability of the
methods used to demonstrate comparability. The comparability exercise should entail
evaluation of both drug substance and drug product. Comparability study must take into
consideration:
the complexity of the molecular structure,
the type of changes introduced in the manufacturing process during development, and
their impact on quality, safety and efficacy.
For the purposes of clarity, any comparability exercise(s) for process changes introduced
during development should be clearly identified and addressed separately from the
comparability exercise versus the reference product.
4
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html
5
http://www.emea.europa.eu/pdfs/human/biosimilar/4934805en.pdf
6
http://www.emea.europa.eu/pdfs/human/bwp/320700en.pdf
the selected reference product to demonstrate similarities and differences between the two
products. Where comparability testing cannot establish similarity or where differences arise,
the outstanding issues must be addressed through supporting preclinical and/or clinical
work.
The non-clinical documentation requirements are adopted from the CHMP Guideline on
Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active
Substance: Non-clinical and Clinical Issues (CHMP/42832/05)7.
The clinical documentation requirements are adopted from the CHMP Guideline on Similar
Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active
Substance: Non-clinical and Clinical Issues (CHMP/42832/05)8.
The requirements depend on the existing knowledge about the reference medicinal product
and the claimed therapeutic indication(s). Available product/disease specific guidelines
should be followed when appropriate. Relevant international guidelines should be referred to
in the design of an appropriate clinical study programme for biosimilar products.
The required clinical data for the comparability study should be generated with the test
product produced with the final manufacturing process and therefore representing the quality
profile of the batches to be commercialised. Any deviation from this is to be justified and
supported by adequate additional data.
The clinical comparability exercise should begin with pharmacokinetic (PK) and
pharmacodynamic (PD) studies followed by clinical efficacy and safety studies.
7
http://www.emea.europa.eu/pdfs/human/biosimilar/4283205en.pdf
8
http://www.emea.europa.eu/pdfs/human/biosimilar/4283205en.pdf
Normally comparative clinical studies are required for the demonstration of clinical
comparability. In certain cases however, comparative PK/PD studies between the biosimilar
product and the reference product may be sufficient to demonstrate clinical comparability,
provided that all the following conditions are met:
The PK of the reference product are well characterised.
There is sufficient knowledge of the PD properties of the reference product, including
binding to its target receptor(s) and intrinsic activity. Sometimes, the mechanism of
action of the biological product will be disease-specific.
The relationship between dose/exposure and response/efficacy of the reference product
is sufficiently characterised.
At least one PD marker is accepted as a surrogate marker for efficacy, and the
relationship between dose/exposure to the product and this surrogate marker is well
known.
For comparative clinical studies to demonstrate clinical comparability between the biosimilar
product and the reference product, clinical comparability margins should be pre-specified
and justified, primarily on clinical grounds.
The conditions of use for the biosimilar product must fall within the directions for use
including indication(s), dosing regimen(s) and patient group(s) for the Singapore reference
product.
In case the reference medicinal product has more than one indication, the efficacy and
safety of the biosimilar product has to be justified or, if necessary, demonstrated separately
for each of the claimed indications. In certain cases it may be possible to extrapolate
therapeutic similarity shown in one indication to other indications of the reference medicinal
product. Justification will depend on e.g., clinical experience, available literature data,
whether or not the same mechanisms of action or the same receptor(s) are involved in all
indications. Possible safety issues in different subpopulations should also be addressed.
Immunogenicity
The ability to predict immunogenicity of a protein product, particularly the more complex
proteins, is extremely limited. Animal studies may not be able to predict how a protein is
likely to behave in humans as immunogenic response is species dependent. Development of
antibodies in some instances is a benign effect causing few, if any, undesirable symptoms in
patients receiving therapy. In other instances, induction of antibodies is associated with
undesirable consequences, which manifest themselves as mild to severe anaphylactoid
reactions. The efficacy may be diminished by induction of neutralising antibodies.
and efficacy in all aspects. It is important to consider the risk of immunogenicity in different
therapeutic indications separately.
Unlike generic chemical drugs, whereby the chemical structure is identical to that of the
reference chemical product, a biosimilar product does not usually have an identical structure
to the reference biological product. Therefore, even though a biosimilar product may be
approved to be similar in terms of quality, safety and efficacy to the reference product,
immunogenicity may preclude switching between products.
A warning statement on the risks associated with switching of products during treatment, and
against product substitution, is to be included in the package insert of the biosimilar product.
6 PHARMACOVIGILANCE REQUIREMENTS
At the time of market approval for a medicinal product, information on the safety of the
product is relatively limited. There are some potential risks which may not have been
identified at the time of market authorization due to several factors like small numbers of
subjects in clinical trials, small study population with specific inclusion criteria and short
duration of exposure. However, when the medicinal product is used more widely in the
postmarket setting, new and unidentified risks associated with the product may emerge. In
addition to the above concerns with medicinal products on the whole, biosimilars may induce
unwanted immune response in treated patients.
The current systems of detecting safety issues relating to medicinal products are applicable
for biosimilar products. In view of the inherent potential of biologics to provoke immunologic
reactions, special care on reporting and assessing of adverse reactions should be taken for
biosimilar products.
The following activities are required in addition to current pharmacovigilance activities for
medicinal products:
9
http://www.emea.europa.eu/pdfs/human/biosimilar/1432706enfin.pdf
In the current framework for medicinal products, the product licence holder has to report
suspected serious ADRs occurring in Singapore to the Pharmacovigilance Branch no later
than 15 days from the first receipt of the reports. For biosimilar products, this reporting by
product licence holder will extend to include the reporting of non-serious adverse reactions
that do not appear in the product label occurring in Singapore as well. This is to enable the
Pharmacovigilance Branch to capture cluster effects of both serious and non-serious ADRs.
(ii) Reviewing of periodic safety update reports (PSURs) for biosimilar products
The product licence holder is required to submit the global PSURs to HSA every 6 monthly
for the first 2 years, followed by yearly for the following 3 years for a biosimilar product that is
newly registered in Singapore. In addition, the product licence holder will be required to
submit the line listings of all the serious and non-serious adverse events in Microsoft Excel
format to the Pharmacovigilance Branch to aid in assessments and reviews, when
requested.
For all biosimilar products, additional monitoring activities need to be in place to address the
safety concerns which these products may bring about, on top of routine pharmacovigilance
activities. The product licence holder is required to submit a risk management plan for the
biosimilar product at the time of application for product licensure. The plan must be with the
intention to mitigate potential risks associated to the biosimilar product.
The product licence holder should provide additional educational materials to the physicians
to provide them with information on the specific risks of the biosimilar product and measures
on how to reduce them.
Patients information leaflets should be prepared by the product licence holder to provide
patients with relevant information on what are the potential risks of the product and what are
the signs and symptoms which they should alert their healthcare providers on.
The product licence holder is required to supply the Pharmacovigilance Branch with the
sales data, in terms of number of units of product sold and the buyer categories (e.g.
restructured hospitals, private hospitals, specialist clinics, general practitioner clinics) of their
biosimilar product on a quarterly basis. These data will be used for an estimation of the
number of local exposures to the product. When requested by HSA, the product licence
holder will be required to provide buyer list of their biosimilar product.
The product licence holder is to submit the following documents prior to import and sale of
each batch of the biosimilar product:
Manufacturers batch release data and certificate of analysis
HSA may also choose to carry out independent batch testing of selected batches based on
the following factors:
No batch release certificate from one of HSAs reference agencies
Unsatisfactory result(s) in the certificate of analysis from a laboratory in one of HSAs
reference agencies or other accredited biologics testing laboratory11
Unsatisfactory inspection history
Unsatisfactory testing history
Unsatisfactory stability data
Post-marketing experience e.g., adverse drug reaction
10
Laboratory in compliance with the latest recommendations from the US FDA, ICH, CHMP and all assays
performed under full compliance with GLP and cGMP standards
11
Laboratory in compliance with the latest recommendations from the US FDA, ICH, CHMP and all assays
performed under full compliance with GLP and cGMP standards