Frequently Asked Questions (FAQs) : BIOEQUIVALENCE
1. Test product
1.1 If the manufacturer of the test product used to conduct a BE study is not the same as the manufacturer of product proposed for registration in Malaysia, can the BE study be accepted to support the registration of the product?
In general, the manufacturer of the product proposed for registration should be the same as the manufacturer of test product (biobatch) used in the BE study. However, a BE study using a test product manufactured by a different manufacturer can be considered to support the registration of a product with following additional supporting data:
The applicant/product registration holder is required to enclose documents ‘i to vii’ in section P9, whereas document ‘viii’ should be enclosed under section P. This requirement is applicable to both registered products and new registration applications. Decision to accept the study and all supporting data will only be concluded upon completion of full evaluation of the product dossier.
- Discussion on similarities & differences between the test product used in BE study (biobatch) and the product proposed for registration in terms of compositions (formula) and characteristics of active ingredient(s) and excipient(s) used.
- Discussion on the finished product specifications between test product used in BE study (biobatch) and the product proposed for registration.
- Discussion on the manufacturing process between the test product used in the BE study (biobatch) and the product proposed for registration. The discussion should include the manufacturing steps involved, equipment used, environmental controls during manufacturing and quality control of the raw materials and the finished product.
- No changes in the manufacturer/ supplier of the active pharmaceutical ingredient (API) for test product used in BE study (biobatch) and the product proposed for registration. Otherwise, applicant should provide discussion on specifications and characteristics of the API(s) to prove that the bioavailability of the finished product remains identical.
- Batch analysis of test product used in BE study (biobatch) and the product proposed for registration using at least pilot batches, at a minimum of three (3) batches for comparison.
- Comparative dissolution profile (CDP) data between batches manufactured at the same site as test product used in BE study (biobatch) and batches manufactured at the proposed site for registration. The CDP should be for at least three (3) batches from each site and conducted according to in-vitro dissolution requirements in the latest ASEAN Guideline for The Conduct of Bioequivalence Study. One of the batches in comparison must be of the test product used in BE study (biobatch).
- Assessment report from any of the DCA reference country regulatory agencies as supporting data to prove that the BE data submitted and site change has been agreed and approved by other regulatory agencies.
- The manufacturing site of the test product used in BE study (biobatch) should have been inspected by a PIC/S participating authority or a competent regulatory authority and has a valid Good Manufacturing Practice (GMP) certificate at the point of submission. The manufacturing site must be listed in the CPP as one of the manufacturing sites of the product.
The applicant/product registration holder is required to enclose documents ‘i to vii’ in section P9, whereas document ‘viii’ should be enclosed under section P. This requirement is applicable to both registered products and new registration applications. Decision to accept the study and all supporting data will only be concluded upon completion of full evaluation of the product dossier.
1.2 If the manufacturer for the active pharmaceutical ingredient (API) of test product used to conduct a BE study is not the same as the API manufacturer of the product proposed for registration in Malaysia, can the BE study be accepted to support the registration of the product?
1.3 If the batch size of the test product used to conduct BE study is larger than the batch size of product proposed for registration in Malaysia, can the BE study be accepted to support the registration application of the product?
2. Product-specific BE requirement
2.1 Are bioequivalence studies required for registration of products containing Cholecalciferol (strength more than 1000IU) as a single ingredient in oral, solid dosage forms?
Bioequivalence studies are not required for all generic products containing Cholecalciferol (more than 1000IU) as a single ingredient in oral, solid dosage forms, since Cholecalciferol is a well-known active substance with an established efficacy and safety profile proven by published scientific literature.
However, the applicant/product registration holder must submit the following data in place of a bioequivalence study report:
However, the applicant/product registration holder must submit the following data in place of a bioequivalence study report:
- Data in support of absorption and safety profile of Vitamin D derived from reviews and publications of recognized bodies
- Clinical overview and justification based on scientific literature on why there is no need to generate additional clinical data
- Discussion/review on the composition of the pharmaceutical preparation especially components that may cause significant difference in absorption and therapeutic profile. Potential differences in the in vivo release properties from different formulations, both for product applied for and those used in the submitted bibliographical documentation, should be discussed.
2.2 Are bioequivalence studies required for registration of generic products containing combination of Tryptophan with other amino acid?
Bioequivalence study is not required for all generic products containing combination of Tryptophan with other amino acid when it is used as supplement, with indication such as:- ‘Prevention and therapy of damages due to faulty or deficient protein metabolism in chronic renal insufficiency in connection with limited protein in food of 40g per day (for adults) and less; i.e. generally in patients with glomerular filtration rate (GFR) between 5 and about 15ml/minutes.’
(Decision: National Working Committee for BE Studies Meeting 1/2014 – 23th April 2014)
(Decision: National Working Committee for BE Studies Meeting 1/2014 – 23th April 2014)
2.3 Are bioequivalence studies required for registration of generic radiopharmaceutical products?
Bioequivalence study is not required for all generic radiopharmaceutical products.
(Decision: National Working Committee for BE Studies Meeting 1/2020 - 28th December 2020)
2.4 What is the BE study requirement for an immediate release tablet/capsule with specific formulation characteristics?
ASEAN Guideline for the Conduct of Bioequivalence Studies (March 2015), 3.1.4 Study conduct, Fasting or fed conditions states that for products with specific formulation characteristics (e.g. microemulsions, solid dispersions), bioequivalence studies performed under both fasted and fed conditions are required unless the product must be taken only in the fasted state or only in the fed state.
Thus, more than 1 BE study may be required to show the interchangeability between an immediate release generic tablet/capsule and comparator product with specific formulation characteristics.
As ASEAN Guideline for the Conduct of Bioequivalence Studies (March 2015) is adopted from Guideline on the Investigation of Bioequivalence (European Medicines Agency, London, 20 January 2010, CPMP/EWP/QWP/1401/98 Rev 1), product registration holder is advised to also refer to EMA product-specific bioequivalence guidance for the information on the number of study required and the study design for a specific product (if available).
(Decision: National Working Committee for BE Studies Meeting 1/2021 - 26th October 2021)
3. In vitro dissolution test
3.1 What are the recommendations for dissolution test of gastro-resistant formulations for the purpose of dissolution profiles comparison?
There are two (2) options in comparing the dissolution profiles of gastro-resistant formulation:
- According to European Medicines Agency (EMA) Questions & Answers: Positions on Specific Questions Addressed to the Pharmacokinetic Working Party (PKWP), 26 June 2015, the in-vitro dissolution test should be conducted following the conditions as below:
- 2 hours in pH 1.2 media followed by 45 minutes in pH 6.8 media
- 2 hours in pH 4.5 media followed by 45 minutes in pH 6.8 media
OR
- According to ASEAN Guideline for the Conduct of Bioequivalence Studies, March 2015, the in-vitro dissolution test should be conducted in three different buffers (pH 1.2, 4.5 and 6.8).
Justifications on the selection of test method and test results should be further discussed and reported.
(Decision: National Working Committee for BE Studies Meeting 1/2016 – 16th June 2016)
