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1.
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What is considered a medicinal product?
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A ‘medicinal product’ refers to any substance or article (not being an instrument, apparatus or appliances) which is manufactured, sold, supplied, imported or exported for use wholly or mainly in the following ways:
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use by being administered to one or more human beings for a medicinal purpose; and/or,
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use as an ingredient in the preparation of a substance or article which is to be administered to one or more human beings for a medicinal purpose.
A ‘medicinal purpose’ means any one or more of the following purposes:
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treating or preventing disease;
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diagnosing disease or ascertaining the existence, degree or extent of a physiological condition;
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contraception;
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inducing anaethesia; and/or,
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otherwise preventing or interfering with the normal operation of a physiological function, whether permanently or temporarily, and whether by way of terminating, reducing or postponing, or increasing or accelerating, the operation of that function or in any other way.
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2.
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What is the procedure to apply for a product licence or to make variations to an existing product licence?
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A product licence is required for import and sale of medicinal products in Singapore. Applications for a product licence and variation application for existing product licences can be made online via PRISM. Specific details on how to fill in the application form and the submission requirements can be found in the Guidance for Medicinal Product Registration in Singapore.
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3.
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What is the required dossier submission format?
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The dossier is to be in the International Conference on Harmonisation (ICH) Common Technical Document (CTD) format or the ASEAN Common Technical Document (ACTD) format.
Structure and content of the ICH CTDformat can be obtained from the ICH website.Structure and content of the ACTD format are detailed in the ACTD guidance documents.
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4.
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What is the submission dossier requirements?
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The dossier requirements for each application will differ, depending on the type of application and type of dossier. The Application Checklists (ICH CTD or ACTD) will serve as a guide to the necessary documents required for submission.
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5.
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For the submission dossier, should the hardcopy or softcopy be submitted?
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An electronic copy of the complete CTD dossier is to be submitted with the application – i.e. Modules 1 to 5 of the ICH CTD or Parts 1 to 4 of the ACTD. A hardcopy is only required for all administrative documents [Module 1 (ICH CTD) or Part 1 (ACTD)].
All administrative documents [Module 1 (ICH CTD) or Part 1 (ACTD)] are to be attached as soft copies into PRISM section 7 (Supporting Attachments).
For the remaining Modules/Parts, applicants can opt to either attach the documents in full into PRISM section 7 (Supporting Attachments) or submit soft copies (e.g. PDF format) of the documents in a CD. However, applicants are advised not to combine PRISM attachments with a CD submission – i.e. all supporting documents must be attached in PRISM or all supporting documents submitted in a CD.
When applicable, upon acceptance, applicants will be notified to submit additional copy(ies) of clinical documents (in CD).
If an electronic copy of the complete CTD dossier is not possible, HSA will accept the complete dossier in hardcopy.
The submission of the complete dossier should take place within 2 working days after the PRISM application submission to prevent delays in processing of the application. The date of submission is defined as the date when HSA receives the complete dataset for the application.
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6.
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What are the application fees, licence fees and evaluation fees payable to HSA for registration of a medicinal product or variation applications for registered products? When should the payment be made, and how?
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For a current list of fees, go to Fees/Service Charges for Licences and Certificates of Western Medicines.
The application fees are separated into screening fee and evaluation fee. Fee invoices for screening are typically generated upon submission of the application in PRISM, while the fees for evaluation are generated upon acceptance of the application.
Application fees are generally charged per application (i.e. per strength, dosage form, etc). However, for applications via the full dossier evaluation route, fees are charged based on per submission (regardless of the number of strengths and/or dosage forms).
For MIV-1 applications, the fee invoice will be generated upon submission, as there is no screening fee for such applications.
Payment is expected within two weeks for all invoices. Payments may be made via GIRO or Payment System Interface (PSI).
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7.
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What are the targeted processing timelines?
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The target processing timelines, from date of acceptance to regulatory decision excluding stop-clock, for the various application types and evaluation routes is detailed in the table below.
Dossier type | Target processing time (working days) | New Drug Application (NDA) | Generic Drug Application (GDA) | Major Variation Application (MAV-1) | Full | 270 | - | 270 | Abridged | 180 | 240 | 180 | Verification | 60 | - | 60 |
The target processing timeline for screening dossiers (NDA, GDA, MAV-1, MIV-1) is 25 working days before the first query is issued. 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.
For MIV-1 applications, the target processing timeline to regulatory decision is 120 working days from the date of receipt of the complete dataset.
For MIV-2 applications, the notification timeline prior to implementation of the variation(s) is 40 working days from the date of submission. The date of dossier submission should be within 2 working days after PRISM submission. The date of submission will be defined as the date when HSA receives the complete dataset for the application.
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8.
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Is there any priority review available for applications and what are the criteria?
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Yes, priority review can be requested for new drug applications submitted via the abridged evaluation route, if the product is a life-saving drug and there are unmet medical needs. The criteria for consideration are as follows:
The medicinal product is intended for treatment of a serious life-threatening condition and demonstrates the potential to address local unmet medical needs, as defined by:
· the absence of a treatment option; or
· the lack of safe and effective alternative treatment, and the drug would be a significant improvement compared to available marketed products, as demonstrated by
(i) evidence of increased effectiveness in treatment, prevention, or diagnosis; or
(ii) elimination or substantial reduction of a treatment-limiting drug reaction.
Disease conditions that are of local public health concerns will be given primary consideration for priority review. Currently these include:
· cancer, and
· infectious diseases: dengue, tuberculosis, hepatitis and malaria.
The request for priority review should be accompanied by justification on why the application concerned 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 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.
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9.
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What is the full dossier evaluation route and how do I submit an application via the full dossier evaluation route?
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The full dossier evaluation route is for products that have not been approved by any competent drug regulatory agency prior to its submission for registration in Singapore. This applies to an innovator product containing a new chemical/biological entity, new combination of chemical/biological entities, or an innovative use of a registered product.
Applicants need to inform the Pharmaceuticals & Biologics Branch (via email to HSA_MedProd_Registration@hsa.gov.sg) two months prior to the intended date of submission to arrange for a pre-submission meeting. The purpose of the meeting is to enable the applicant to discuss the proposed full dossier submission and to obtain procedural advice. To facilitate preparation for evaluation, background of the product should be presented before and at the meeting.
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10.
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My product is a combination of a medical device and a drug. How should I submit my product for registration?
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The type of application to be submitted depends on the primary function of the product. If the product’s primary function is a device and the drug has an ancillary function, the application should be submitted to the Medical Device Branch for evaluation. If the drug has the primary function and the device is ancillary, the application should be submitted to Pharmaceuticals & Biologics Branch for evaluation.
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11.
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Can I submit an application for a product which has not been approved in the country of origin?
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12.
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I have a pending variation application. Can I submit another variation application?
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You can submit 3 MIV-1 applications concurrently. At the current moment, for MAV-1 and MIV-2 applications, you can only submit 1 application at any one time.
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1.
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What stability studies need to be conducted for registration in Singapore?
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2.
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Why is the ASEAN Guideline being implemented?
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Conducting stability studies under the ASEAN Guideline will demonstrate whether the drug product will maintain its quality when transported, stored and used under “normal” environmental conditions – i.e. under 30C/75%RH (Zone IV climatic) conditions.
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3.
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What if stability data under Zone IV climatic conditions is not available for submission after 1 January 2009?
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Applications with stability data that does not follow ASEAN guidelines will still be accepted but the following documents must be included in dossier section P8:
(a) a stability protocol that follows the ASEAN guidelines, and,
(b) a commitment letter to provide all available stability data following the updated protocol in point (a) above within 6 months from the submission date.
Applications following this route will be subjected to a post-approval licensing condition upon regulatory approval.
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4.
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For solutions in semi-permeable container closure systems, is 30ºC/75% real-time stability data required for product registration?
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HSA's approach will be to evaluate all stability protocols and data as per the ASEAN Guidelines. However, deviations from the ASEAN Guidelines are permissible provided that scientific evidence is provided to explain and justify the deviation(s). HSA reserves the right to request for appropriate information as deemed necessary.
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5.
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What if the drug product is not stable at 30ºC/75%RH?
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If the product is not stable at 30ºC/75%RH, then this would be one example to justify deviation from the ASEAN Guideline. However, full scientific analysis and explanations that demonstrate the product’s instability under 30ºC/75% must also be submitted.
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6.
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How will the ASEAN Guidelines affect the product labels?
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HSA’s approach has always been to have the storage condition and shelf-life labelled according to the submitted stability data. However, with the implementation, HSA will also have an added approach towards aligning the storage condition labelling with the ASEAN guidelines – i.e. “Store at or below 30ºC”. The reason for this approach is to provide assurance to the patients that the product’s quality can be maintained during “normal” usage and storage.
If the stability data follows the ASEAN guidelines, then there is no real issue – the product should be labelled “Store at or below 30ºC”.
If the stability data follows the ASEAN guidelines but the product label does not, justification must be provided to explain the reason(s) for deviating from the guidelines. HSA still reserves the right to request for alignment of the labels if deemed appropriate.
If the stability data does not follow the ASEAN guidelines, then the proposed storage condition, “Store at or below 25ºC”, will be acceptable. However, a post-approval licensing condition to submit an MIV to change the storage condition labelling prior to the next licence renewal will be inserted upon regulatory approval.
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7.
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How will the ASEAN Guideline implementation on 1 January 2009 affect existing products?
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The storage condition and shelf-life of existing registered products will remain as status quo.
However, for minor variation (MIV) applications that require submission of stability data, the protocol and data must follow the ASEAN guidelines. An exception to this is an MIV application to extend the product’s shelf-life – the storage condition can remain status quo IF the submitted stability protocol of the MIV application is the same as what had been previously registered.
If there are any doubts or questions about whether the ASEAN guidelines apply to the MIV, please submit an MIV Submission and Inquiry Form in Appendix 13 of the updated Guidance on Medicinal Product Registration in Singapore (Jan 2009).
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1.
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Which sections of SQOS are required if I submit a CEP to support the drug substance information?
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If the applicant claims that the drug substance (DS) will comply with European Pharmacopoeia (EP), in the Singapore QOS indicate CEP number in S1, details of manufacturer in S2.1 and details of the specifications in S4.4. If the DS does not comply with EP, indicate CEP number in S1, details of manufacturer in S2.1 and details of the control of drug substance in S4.1-S4.5. In either case, additional data not addressed in the CEP, such as stability data (S7) if the re-test period is not stated on the CEP and other physico-chemical characteristics, if applicable are also required and should be indicated in the appropriate section(s). In addition to the SQOS, the relevant sections of the CTD are required as well.
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2.
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Characterisation of Impurities for Finished Drug Product. What if there is none known? I.e. not documented in pharmacopoeia?
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Indicate “none known”, However there should be a control for any impurities indicated in the pharmacopeia.
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3.
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Are Sections P4.1 Specifications, P4.2 Analytical Procedures, P4.3 Validation of Analytical Procedures only applicable to non-compendial excipients and for compendial excipients which include supplementary tests?
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4.
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Once 3 consecutive batches have been submitted for Process Validation, do we still need to provide Formulation Development (P2.2.1) and manufacturing Process Development (P2.3)?
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Sections Formulation Development (P2.2.1) and Manufacturing Process Development (P2.3) are parts of the CTD, hence, are required to be submitted although 3 consecutive batches have been submitted for Process Validation.
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1.
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Is there a need for bridging studies or local trials to be conducted either pre-submission or post-approval?
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Bridging studies or local trials are not compulsory provided that the submitted data is sufficient. Reference should be made to the ICH E5 Guidelines.
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2.
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My product is a non-prescription medicine. Do I need to submit the full clinical data for registration?
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For submission of a NDA or MAV-1 application for a non-prescription medicine (P or GSL), request for waiver of clinical data submission may be made if the application fulfils the eligibility criteria stipulated. Details of the eligibility criteria and the dossier requirements are detailed in the Guideline on Submission for Non-Prescription Medicinal Products.
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1.
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How do I identify an appropriate Singapore reference product for my generic product?
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Applicants are advised to search HSA’s online database to identify the Singapore reference product. The Singapore reference product must be a currently registered product and be the same pharmaceutical dosage form and strength as the proposed generic drug.
The applicant is advised to contact PBB 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 a scientific justification for PBB’s consideration. However, a generic drug application for a higher strength than the Singapore reference product will not be accepted.
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2.
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If the dosage form of the generic product is different from the Singapore reference product, is it possible to submit the application as a generic drug application (GDA)?
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This is acceptable if the generic product is a tablet and the Singapore reference product is a capsule, or vice versa. For other dosage forms, the application should be submitted as a new drug application (NDA).
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3.
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For a lower strength GDA application, is it possible to submit a bioequivalence study conducted using a higher strength generic product?
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This is acceptable only if the pharmacokinetic profiles are linear or proportional and proper justification is given. The corresponding higher strength reference product should also be registered in Singapore.
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1.
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Specific enquiries or clarifications on medicinal product registration can be sent to HSA_MedProd_Registration@hsa.gov.sg.
For issues relating to minor variation application submission, you may also opt to fax or email a completed MIV Filing and Submission Inquiry Form to HSA.
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Pharmaceuticals & Biologics Branch
Health Products Regulation Group
11 Biopolis Way #11-03 Helios
Singapore 138667
Tel: (65) 6866 3437/17
Fax: (65) 6478 9032/31
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1.
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1. How will the applicants be notified of the stage of their applications?
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Application Status Notification will be transmitted either via email or fax, (depending on the applicants’ preferred mode of contact) to inform them of the following stages of their applications submitted on or after 15 April 2009:
(a) When application is accepted for evaluation
(b) When application has progressed to active evaluation
(c) When evaluation is at the midway stage
(d) When the evaluation is completed and is in the regulatory decision phase
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2.
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2. Will the Application Status Notification apply to all type of applications relating to drug registration?
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The Application Status Notification Scheme is applicable to the following application types:
(a) NDA (Full Dossier)
(b) MAV (Full Dossier)
(c) NDA-1 (Abridged Dossier)
(d) NDA-2 (Abridged Dossier)
(e) NDA-3 (Abridged Dossier)
(f) GDA-1
(g) GDA-2
(h) MAV-1 (Abridged Dossier)
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3.
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3. How can I opt for the Progressive Payment Scheme for my applications?
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You can opt for the Progressive Payment Scheme when you are submitting your application via PRISM, provided your company has a GIRO account with HSA.
For all Full Dossier applications, your company does not need to have a GIRO account with HSA as the payment will be handed offline.
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4.
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4. How many stages are allowed under the Progressive Payment Scheme?
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Under the Progressive Payment Scheme, the following are the stage payment are deducted through the companies’ GIRO accounts:
(a) 30% when your application is accepted for evaluation
(b) 40% when your application is at the active evaluation stage
(c) 20% when your application is midway through the evaluation
(d) 10% when the evaluation of your application is completed and moved to the regulatory decision phase
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5.
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5. If I withdrew my application after it has been accepted for evaluation, will I have to pay for the evaluation fee remaining stage of evaluation?
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You need not have to pay for evaluation fee for the remaining stage of the evaluation if you withdrew your application before it progress to the next stage of evaluation.
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6.
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6. My company does not have a GIRO account with HSA, can I opt for the Progressive Payment Scheme when submitting my applications?
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You will not be able to opt for the Progressive Payment Scheme when submitting your applications if your company does not have a GIRO with HSA. You are advised to open a GIRO account with HSA to enjoy the convenience and benefits of the Progressive Payment Scheme.
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7.
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7. Can I opt for the Progressive Payment Scheme after I have submitted my application in PRISM?
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You will not be able to opt for the Progressive Payment Scheme after you have submitted your application in PRISM. Therefore, we would like to advise you to make the decision before you submit your application.
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