Common Questions related to generic drug applications

Question 1:
We are planning to submit a generic version of X but the original Singapore Reference Product is de-registered. Which of the currently registered products should be the SRP? 

Answer 1:
If a reference product (innovator) is not available, an alternate registered comparator product may be used if adequately justified (e.g. a registered generic therapeutic product widely used by local hospitals) by the applicant. The acceptability of the justification will be determined during the screening stage of the application. HSA does not provide confirmatory advice on the choice of a specific SRP prior to application submission.  You may refer to Sections 16.1 and 16.2 of the Guidance on Therapeutic Product Registration in Singapore for more information on Singapore Reference Product.

Question 2:

We're planning to submit GDA-1 application for product C. However, the originator product is no longer registered and now there are only several generics registered. The reference product that we used in product development and in the BE study is the originator product sourced overseas. Kindly advise if we can use the existing BE study supplemented with comparative dissolution studies conducted between one of the currently registered products in Singapore against the BE reference product.

Answer 2:

The BE study performed between the proposed generic and the originator product from overseas can be accepted. In this case, comparative dissolution studies should be provided between the BE reference product and one of the registered generic products in Singapore. Justifications for your choice of the registered generic used in the comparative dissolution studies should be provided. You should also indicate this generic as the alternate SRP in your PRISM application.

Please refer to Appendix 10 Product Interchangeability and Biowaiver Request for Chemical Generic Drug Applications for information regarding BE study and comparative dissolution profile testing requirements for GDAs.

Please note that the final acceptability of the BE study can only be determined during screening and/or evaluation of the GDA when the complete dataset is received and reviewed.

Question 3:

Our company’s product’s dossier was compiled based on the reference product: X Tablet 1mg (SIN12345P) which was verified as a registered therapeutic product during the start of the dossier compilation. However, we notice that this product has been removed from the HSA registered TP database and we were planning to submit the GDA soon. Kindly clarify if we are able to proceed with the GDA with X Tablet 1mg (SIN12345P) as the Singapore Reference Product.

Answer 3:

We can consider X Tablet 1mg as the Singapore Reference Product for your GDA application as long as the application is filed within 1 year of its removal from the Register of Therapeutic Products. HSA does not provide confirmatory advice on the choice of a specific SRP prior to application submission. 

Question 4:

My company is interested to register generic DRUG X Tablet 5 mg. However, based on the current local market surveys, the SRP is no longer marketed in Singapore. Hence, please advise on the appropriate reference product in this situation.

Answer 4:

If you are unable to procure the SRP locally for the necessary studies although it is still registered, you may  source the SRP-equivalent from overseas markets, i.e. manufactured at the same drug product manufacturing site as the SRP.

Question 1:
Could I apply for generic drug registration if the strength is higher than the registered innovator product? 

Answer 1:
The proposed application may be submitted as a GDA if the use of the proposed strength falls within the current approved dosing regimen of the SRP. Please indicate the registered innovator product as the SRP in your PRISM application. Please refer to the Register of Therapeutic Products for the current package insert of the SRP for more information regarding the conditions of use of the SRP.

Question 2:

My company is interested to register S Injection 0.5mg/ml supplied as a 1ml ampoule, but the SRP strength is 5 mg/5mL only. Can I submit a GDA for my product?

Answer 2:

You may submit a GDA for a product of a lower strength than the SRP if the use of the proposed product strength falls within the current approved dosing regimen of the SRP. Please indicate the registered innovator product as the SRP in your PRISM application.

Please refer to the Register of Therapeutic Products for the current package insert of the SRP for more information regarding the conditions of use of the SRP.

Question 1:

Can I submit a GDA for a concentrate for solution for injection of Drug X when the SRP is a powder for solution for infusion?

Answer 1:

You may submit a GDA for the proposed generic if it is in the same final pharmaceutical dosage form (injectable solution) and has the same concentration as the SRP at the point of administration.

Question 2:

Can I submit a GDA for oral granules when the SRP is an oral solution?

Answer 2:

You may submit a GDA for the proposed generic if it is in the same final pharmaceutical dosage form (oral solution) and has the same concentration as the SRP at the point of administration.

Question 3:

Can I submit a GDA for an immediate release tablet when the SRP is an immediate release capsule?

Answer 3:

Immediate release tablets and capsules are considered to be of the same dosage form. You may submit the proposed product as a GDA. 

Question 1:

We would like to conduct a BE study for Drug X Tablet 300 mg using the SRP Tablet 300 mg. We noted that there are 2 registered drug product manufacturing sites for the SRP in the HSA register. Which manufacturing site should the BE reference product be from?

Answer 1:

For the BE reference product to be considered equivalent to the SRP, it can be from either drug product manufacturing site.

Question 2:

The country of manufacture of the BE RP is the same as that of the SRP, however, the full manufacturer's address is not indicated on the BE RP product labelling. Will HSA accept that the BE RP is the same as the SRP based on this justification?

Answer 2:

If you are unable to demonstrate that the BE RP was manufactured at the Singapore-registered drug product manufacturing site, the BE RP will be considered different to the Singapore reference product and you should refer to Appendix 10  of the Guidance on Therapeutic Product Registration in Singapore for the required documentation to support the comparability of the BE reference product to the SRP.

Question 1:

We would like to purchase the Singapore Reference Product for dissolution testing to support our GDA. However, it is a Prescription Only Medicine (POM) and not allowed to be purchased over-the-counter or via a pharmacist. Please advise how we can obtain the SRP, especially as we would need a large quantity.

Answer 1:

If you are procuring the SRP in Singapore for the purpose of conducting comparative dissolution profile testing, and not for human use, you may procure it from a licensed wholesaler/pharmacy.

Question 1:

We would like to register drug X 10 mg, 20 mg and 40 mg with the BE study conducted with the 80 mg product strength. However, we are not planning to submit the 80 mg for registration. Is this BE study (80 mg) acceptable?

Answer 1:

A study on a higher strength than proposed for registration is acceptable provided that the biowaiver criteria for additional (non-study) strengths are fulfilled. Please refer to section 3.1.6 of the ASEAN Guideline for the Conduct of Bioequivalence Studies [PDF, 606 KB] for more information regarding the general biowaiver criteria for multiple strengths.

Question 1:

Does HSA approve BE studies based on a list of accredited BE centres?

Answer 1:

There is currently no pre-requisite for  accreditation of BE study centres.  BE studies submitted in support of generic drug applications are required to be conducted in compliance with Good Clinical Practice (GCP) and the related ICH E3 guideline. This may be demonstrated with BE site inspection report(s) from national drug regulatory agencies or WHO.

Question 1:

Can you please confirm that drug X is a BCS Class I drug?

Answer 1:

You may refer to the ICH M9 Guideline (Biopharmaceutics Classification System-based Biowaivers) [PDF, 227 KB] for the requirements for BCS-based biowaivers, including requirements for demonstrating the BCS classification of drug substances. HSA does not provide confirmatory advice prior to application submission.

Question 2:

My company is interested to register Drug X Tablet 100 mg. According to the FDA guidance, this is a BCS Class III drug and is eligible for a biowaiver. Can I also apply for a BCS-based biowaiver in Singapore?

Answer 2:

A BCS-based biowaiver can be considered to support the registration of the application if the submitted data are adequate to fulfil the published criteria for the relevant BCS Class in terms of the drug substance and drug product. You may refer to the ICH M9 Guideline (Biopharmaceutics Classification System-based Biowaivers) [PDF, 227 KB] for more details regarding the requirements.

Question 3:

I am interested in submitting a GDA via BCS-based biowaiver. How can I obtain information on the quantitative composition of the SRP?

Answer 3:

In general, the manufacturer of the generic product is expected to analyse the quality attributes of the reference product, including its formulation for benchmarking purposes. You may wish to consult the generic drug product manufacturer for advice.

Question 1:

I have checked Appendix 10 of your guidance and it is stated that “In vivo BE data are required to support GDAs for Prescription Only Medicines (POM) in oral solid dosage forms.” Therefore, may I confirm with HSA that BE study data is not required for other generic products?

Answer 1: 

As stated in section 4.1 of Appendix 10 of the Guidance on Therapeutic Product Registration in Singapore, BE data or biowaiver justifications are not required for the listed drug product types. For products not included in the list, justifications for requesting a biowaiver is required, otherwise BE data should be provided to support your GDA.

Question 1:

We would like to register generic products 40 mg and 80 mg. Although the SRP is registered in both of these strengths, we have not been able to find the 80 mg strength locally and it seems that it is no longer marketed. Can we conduct the comparative dissolution studies on the SRP 40 mg or must we use an alternative SRP 80 mg?

Answer 1:

In the event of difficulty in sourcing for the matching strength of the SRP locally or the SRP-equivalent overseas, you may consider using 2 units of SRP 40 mg in lieu of 1 unit of SRP 80 mg to conduct the necessary comparative dissolution studies.

Question 2:

As the BE reference product (BE RP) is manufactured at a different site from the Singapore reference product (SRP), we will need to conduct comparative dissolution profile testing between the BE RP and SRP. However, the BE RP had already expired. What can we do to bridge the BE RP to the SRP?

Answer 2:

In the event that the BE RP had already expired, you can consider sourcing for a newer batch of reference product manufactured at the same manufacturing site as the BE RP (i.e. ‘BE RP equivalent)’.  Please include a copy of the product labels of the BE RP equivalent with the application submission for verification purposes.