Follow Us: social media social media social media    Language :           

Bioequivalence (BE)

  • In line with the Ministry of Health objectives of ensuring quality, efficacy and safety of pharmaceutical products that are marketed, the Drug Control Authority at its 92nd Meeting has decided to review the registration of generic products to include Bioequivalence (BE) studies requirements for certain categories oral immediate release products.

    Bioavailability (BA) testing of drug products in humans provides the most appropriate method available for determining bioequivalence. Two drug products are considered bioequivalent if they are pharmaceutically equivalent and their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, can be expected to be essentially the same.

    The Working Committee for BE Studies which was formed in September 1999, comprising of representatives from University Malaya (UM), Universiti Sains Malaysia (USM), Universiti Kebangsaan Malaysia (UKM), International Medical University (IMU), National Pharmaceutical Regulatory Agency (NPRA) and the pharmaceutical industry. The members were officially appointed to undertake the task of formulating an action plan for the conduct of BE studies in Malaysia through collaborative efforts.

    Publication of the 'Malaysian Guidelines for the Conduct of Bioavailability and Bioequivalence Studies' marked the first outcome of this committee's objectives. This guideline is to provide guidance to the local researchers in conducting BE Studies in accordance to established international standards. Implementation of this guideline will promote properly designed studies being carried out.


    STATUS OF IMPLEMENTATION OF BIOAVAILABILITY AND BIOEQUIVALENCE (BA/BE) REQUIREMENTS IN ASEAN

    The ASEAN Guideline For The Conduct of Bioavailability / Bioequivalence (BA/BE) Studies was adopted at the 8th ASEAN Consultative Committee on Standards and Quality - Pharmaceutical Product Working Group (ACCSQ - PPWG) Meeting in Bangkok. Malaysia has conducted surveys in 2004 and 2005 on BA/BE Studies and its implementation in ASEAN countries. Results of the survey showed that most ASEAN countries require BE studies on certain products based on various criteria and availability of identical innovator product on local market/ASEAN market. However, not all BE centres are being accredited and acceptance criteria of foreign BE studies varies from country to country.

    The 8th ACCSQ - PPWG Meeting has also agreed on possible development of sectoral Mutual Recognition Arrangements (MRAs) for the ASEAN pharmaceutical sector and this includes BA/BE Studies. The 9th Meeting was of the view that the harmonisation of BA/BE is important as it would enable Member Countries to work towards the mutual acceptance of the BA/BE Study Report in ASEAN. ASEAN at this stage should look into harmonisation on the Definition of a Comparator Product/ASEAN Comparator Product, Decision Tree in Determining Comparator Products at ASEAN and National Level and List of ASEAN Comparator Products. In view of this, the 10th ACCSQ - PPWG has appointed a Task Force consisting of representatives from all Member Countries to follow up on the recommendations. The Taskforce is led by Indonesia and assisted by Malaysia.

    The 10th meeting also encouraged Member Countries to look into the acceptance of the BE Studies conducted by recognized BE Centres in the region in order to reduce unnecessary repetition of BE Studies and transaction cost for industry. The Meeting encouraged Member Countries without adequate BE facilities at this moment to use the available BE facilities in other countries in the region. Member Countries were also requested to look into the accreditation of BA/BE Centres.

    The 13th ACCSQ - PPWG held on 23rd - 27th July 2007 in Kuala Lumpur, Malaysia has endorsed the following recommendations made by the Task Force:

    1. To use WHO Definition for ASEAN Comparator Product i.e. 'A Pharmaceutical product with which the multi-source product is intended to be interchangeable in clinical practice.'
    2. The selection of comparator product is as follows:
    • Innovator product and multiple manufacturing sites of the same innovator registered in the country is acceptable.
    • If the innovator product used as comparator is not registered in the country, justification is required from the generic company to prove its interchangeability with the registered innovator (in vitro or in vivo).
    • If the innovator product cannot be identified, the choice of comparator must be made carefully and be comprehensively justified by the applicant. The selection criteria of a comparator in order of preference are:

    - Approval in ICH and associated countries
    - Pre-qualified by WHO

    A well selected comparator must conform to compendial quality standards, if applicable.
    In view of this, the List of ASEAN Comparator Product is not necessary because the principle of comparator selection has been agreed by all member countries, in accordance with WHO Guidance in TRS 937, 2006, Annex 7.

    The 14th ACCSQ-PPWG held on 18th – 22nd February 2008 in Vientiane,Lao PDR has agreed that Malaysia as Lead Country for BA/BE will continue to lead discussions on the technical guidelines on BA/BE.

    The 15th ACCSQ - PPWG held on 28th – 31st July 2008 in Jerudong, Brunei Darussalam in it’s 1st technical working group (TWG) meeting on ASEAN Bioavailability/Bioequivalence (BA/BE) has deliberated the drafts on Questions & Answers (Q & A) and revision/amendment of the BA/BE Guidelines. The meeting has agreed on the proposed Q & A (version 1) and proposals on editorial corrections to the guidelines. The meeting encouraged Member States to submit proposals for Q & A and revision/amendments to the BA/BE guidelines to Malaysia in accordance with the updating and revision of the guidelines. The meeting has also discussed the Framework for Mutual Acceptance of the BA/BE Study Report in ASEAN and agreed on the following:

    • ASEAN Bioequivalence Study Reporting Format
    • Acceptable conformance standards on the clinical and bioanalytical aspects of BE studies as follows:
    • The clinical standard is ICH GCP E6 guidelines
    • The bioanalytical standard should follow applicable GLP principles
    • To achieve the acceptable criteria for inspection on BA/BE studies, the following steps will be taken:
    • Establishment of minimum inspection criteria for Member States including checklist
    • Capacity building for inspection
    • Inspection by respective Drug Regulatory Agencies (DRAs)

    The 16th and 17 th ACCSQ - PPWG noted that the BA/BE Taskforce has agreed on the following:

    • The acceptable minimum inspection criteria will be developed based on the EMA SOP for conducting GCP inspection and other relevant references
    • The SOP for conducting inspection of BA/BE studies on clinical and bioanalytical aspects will be incorporated into one document
    • Checklist as a tool for conducting inspection of BA/BE studies will be revised based on SOP developed
    • To achieve the conformance standards on the clinical and bioanalytical aspects of BA/BE Studies

    The next action plan is to development a framework for mutual acceptance of the BA/BE and explore the possibility of organising capacity building programmes for inspection of BA/BE among Member States.

    For presentation slide on Implementation of Bioequivalence Study for Generic Medicine in Malaysia, click here.


  • ASEAN Guideline for The Conduct of Bioequivalence Studies

    The 22nd ASEAN Consultative Committee for Standards and Quality Pharmaceutical Product Working Group (ACCSQ-PPWG) meeting held on 09th -13th March 2015 in Vientiane,Lao PDR has endorsed the 4th draft of 1st revision for ASEAN Guideline for The Conduct of Bioequivalence Studies.

    This latest guideline is adopted from the Guideline on the Investigation of Bioequivalence” (European Medicines Agency, London, 20 January 2010, CPMP/EWP/QWP/1401/98 Rev 1) with some adaptation for ASEAN application.

    Malaysia has fully adopted this guideline since March 2015 and it is the most current guide for the conduct of bioequivalence studies.This guideline is to be read in conjunction with all relevant directives, circulars and updates regarding bioavailability and bioequivalence studies.
    Malaysian Guidance on Biopharmaceutics Classification System (BCS) - Based Biowaiver

    Effective from 1st March 2013, a biowaiver may be granted for generic immediate release oral solid dosage form products containing BCS Class I active ingredients listed in the Guidance On Biopharmaceutics Classification System (BCS) – Based Biowaiver documents. BCS Based biowaiver takes the three major factors that govern the rate and extent of drug absorption from immediate-release solid dosage forms into account i.e solubility and permeability of the drug substance/ active pharmaceutical ingredient (API), and dissolution characteristics of the drug product. This BCS approach provides an opportunity to waive in vivo pharmacokinetic bioequivalence testing for certain categories of immediate-release drug products.

    Malaysian Guidance on Biopharmaceutics Classification System (BCS) - Based Biowaiver guideline is adopted mainly from the following guidelines to suit local requirements:

    Guideline On The Investigation Of Bioequivalence (European Medicines Agency, London, 20 January 2010, CPMP/EWP/QWP/1401/98 Rev. 1/Corr)
    Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (World Health Organization (WHO), Technical Report Series, No 937, 2006)
    Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms (World Health Organization (WHO), Technical Report Series, No 937, 2006)

    Previous BE Guidance Document:

      These two guidances/guidelines were adopted by Malaysia before March 2015 and are no longer in use.


  • Click the following PDF documents to view or download:
    Document Name Download
    1st Generic Immediate Release Product List (March 2017)
    2nd Generic Immediate Release Product List (March 2017)
    3rd Generic Immediate Release Product List (March 2017)
    4th Generic Immediate Release Product List (March 2017)
    5th Generic Immediate Release Product List (March 2017)
    6th Generic Immediate Release Product List (August 2017)
    7th Generic Immediate Release Product List (March 2017)
    8th Generic Immediate Release Product List (August 2017)
    9th Generic Immediate Release Product List (August 2017)
    Bioequivalence Requirements According to 1st - 9th List (Active Ingredients arranged in alphabetical orders) (December 2011)
    List of Comparator Products For Bioequivalence Studies (November 2017)
    List of Comparator Products For Fixed Dose Combination (November 2017)
    The Implementation on Antiviral (ARV) Drug (November 2017)
    List of Comparator Products in Dosage Forms of Effervescents, Dispersible, Orodispersible, Sublingual, Lozenges, Buccal and Chewable Tablets/Capsules (March 2017)
    Product containing combination of amino acid
    Comparative Dissolution Profile (CDP) Between Generic Product and Comparator Product with Gastro-Resistance Formulation
    3 Ways and 4 Ways Bioequivalence Studies Design
    Buletin Ubat-Ubatan - April 2003 (ARV Drug)


    (Last updated: August 2016)

     
  • BE Centres that are listed in Bioequivalence Centre Compliance Programme, National Pharmaceutical Regulatory Agency, Ministry of Health, Malaysia as of 28 November 2017.

    MALAYSIA LOCAL BE CENTRES

     

    FOREIGN BE CENTRES

     
  • GENERIC PRODUCTS CONTAINING DRUG SUBSTANCES/ ACTIVE PHARMACEUTICAL INGREDIENTS (API) THAT MAY BE CONSIDERED FOR BIOWAIVER

    The main aim in conducting a bioequivalence (BE) study is to demonstrate that the active substance in a generic product is absorbed into the body at the same rate and amount as in the comparator/innovator product .This ensures that the generic medicine product delivers the same therapeutic effect as the comparator/innovator product and can be interchangeable without any significant change in the efficacy of the medication.

    However, in certain circumstances, waivers of BE study (biowaiver) can be considered for orally administered generic products in the form of oral solid dosage form.

    A biowaiver may be granted based on the following:

    The biowaivers considered involved products containing the Drug Substance / Active Pharmaceutical Ingredients as listed in the table below:-


    LIST A LIST B LIST C
    • Allopurinol 
    • Amiloride hydrochloride 
    • Cyclophosphamide 
    • Chloroquine sulfate 
    • Levonorgestrel 
    • Norethisterone 
    • Proguanil hydrochloride 
    • Acetazolamide
    • Allyoestrenol
    • Allopurinol + benzbromarone
    • Bacampicillin 
    • Betamethasone
    • Bezafibrate
    • Buclizine
    • Carbinoxamine
    • Carbinoxamine Maleate + Pseudoephedrine HCl
    • Chloramphenicol
    • Chlordiazepoxide
    • Chlordiazepoxide + Clidinium
    • Chloroquine Phosphate
    • Chlorthalidone
    • Chlorzoxazone
    • Clenbuterol HCl
    • Cloperastin HCl
    • Colchicine
    • Cycloserine
    • Dapsone
    • Dexamethasone 
    • Dimenhydrinate 
    • Diphenoxylate HCl+ Atropine Sulphate
    • Dipyridamole
    • Ephedrine HCl + Theophylline
    • Erythromycin Stearate 
    • Ethambutol
    • Flucloxacillin
    • Fludrocortisone Acetate
    • Imipramine HCl
    • L-tryptophan
    • Lithium Carbonate 
    • Meclozine 
    • Methimazole
    • Methyldopa
    • Nitrazepam 
    • Nortriptyline 
    • Phenobarbitone
    • Phenylephrine
    • Prednisolone
    • Primaquine diphosphate
    • Probenecid
    • Prochlorperazine
    • Promethazine
    • Propylthiouracil
    • Quinine sulfate
    • Tolbutamide
    • Triamcinolone
    • Tripolidine hcl
    • Uracil 224mg + Tegafur 100mg
    • Venlafaxine
    • Verapamil
    • Nystatin 
    • Sevelamer Carbonate 
    • Phentermine Hydrochloride 
    • Phenytoin Sodium 
    • Gliclazide
    • Mefenamic Acid
    • Chlorpheniramine Maleate
    • Chlorpheniramine Maleate + Paracetamol
    • Chlorpheniramine Maleate + Phenylephrine HCl
    • Chlorpheniramine Maleate + Phenylephrine HCl + Paracetamol
    • Chlorpheniramine Maleate + Pseudoephedrine HCl + Paracetamol
    • Dexchlorpheniramine Maleate
    • Dexchlorpheniramine Maleate + Pseudoephedrine HCl
    • Dexchlorpheniramine Maleate + Pseudoephedrine HCl + Paracetamol
    • Orphenadrine Citrate
    • Dextromethorphan HBr + Phenylephedrine HCl + Paracetamol
    • Dextromethorphan HBr + Pseudoephedrine HCl + Paracetamol

    Note: These lists are not exhaustive and will be reviewed based on discussions by the National Working Committee for BE Studies and consent from the Drug Control Authority (DCA) as and when needed



    I. Biopharmaceutics Classification System (BCS) - Based Biowaiver

    Effective 1st March 2013, a biowaiver may be granted to generic immediate release oral solid dosage form products containing BCS Class I active ingredients listed in the Guidance On Biopharmaceutics Classification System (BCS) – Based Biowaiver documents. BCS Based biowaivers takes the three major factors that govern the rate and extent of drug absorption from immediate-release solid dosage forms into account i.e solubility and permeability of the drug substance/ active pharmaceutical ingredient (API), and dissolution characteristics of the drug product. This BCS approach provides an opportunity to waive in vivo pharmacokinetic bioequivalence testing for certain categories of immediate-release drug products.


    LIST A

    Generic products containing drug substances/API listed in List A currently can be considered for BCS - based biowaivers:
    1. Allopurinol
    2. Amiloride hydrochloride
    3. Cyclophosphamide
    4. Chloroquine sulfate
    5. Levonorgestrel
    6. Norethisterone
    7. Proguanil hydrochloride

    Note:
    • This list is not exhaustive and will be reviewed from time to time according to the WHO Model List of Essential Medicines and upon scientific judgement and patient risk assessment by the National Pharmaceutical Regulatory Agency (NPRA).
    • BCS-Based Biowaivers will NOT be granted automatically to generic products containing the listed drug substances/API. It will be subjected to the completeness and fulfillment of the requirements and supporting data/documents submitted/required.
    For more information, kindly refer to the Malaysian "Guidance on Biopharmaceutics Classification System (BCS)-Based Biowaiver" (Direktif Arahan di Bawah Peraturan 29, Peraturan-peraturan Kawalan Dadah dan Kosmetik 1984 Bil. 1 Tahun 2013, 28 Februari 2013Bil (101) dlm BPFK/PPP/01/03 Jld 2).


    II. Biowaivers granted based on unavailability/ inaccessibility of comparator/innovator product

    There have been issues on the unavailability/ inaccessibility of comparator/innovator products for certain active ingredients since the implementation of the BE requirement whereby the comparator/innovator product is no longer available in Malaysia. Nonetheless, the comparator/innovator product may be still available worldwide.

    The Drug Control Authority (DCA) at its 171stmeeting (30thJune 2005) approved the proposal by the National Working Committee for BE Studies to give exemption from submitting BE studies (biowaiver) due to unavailability of the comparator product for a few drug substances/active pharmaceutical ingredients. Issues on the unavailability/ inaccessibility of comparators have been dealt as a case to case basis by the National Working Committee for BE Studies. The National Working Committee for BE Studies is mandated to not only assist and facilitate the conduct of BE Studies in Malaysia but also to discuss BE related problems and to formulate recommendation and solutions to these problems.

    BE studies that are conducted using comparator/innovator products that are no longer available in Malaysia will defeat the purpose/ultimate objective in demonstrating interchangeability between generic products and comparator/innovator products that are available in Malaysia.

    The Drug Control Authority (DCA) at its 271st meeting (16th December 2013) approved the proposal that generic products may/will be granted biowaiver if it fulfills ALL of the following criteria:
    1. The comparator / innovator product has been registered with DCA before the implementation of the requirement for bioequivalence studies that is before 1999 and the registration status of the said comparator / innovator product is either cancel, withdrawn, terminated or expired
    2. The comparator / innovator product is not available in Malaysia (verified by the Product Registration Holder) and its sourcing issue/problem has been discussed in the National Working Committee for BE Studies meeting.
    3. The ASEAN selection criteria for comparators as well as the criteria that have been practiced in Malaysia are not applicable.
      • According to the ASEAN selection criteria, a comparator that can be chosen is based in the following order: 
        1. Innovator product 
        2. If the innovator product cannot be identified, the selection of a comparator in order of preference are 
          • Approval in ICH and associated countries (e.g. European Union (EU), United States of America (USA), Japan, Australia & Canada) 
          • Pre-qualified by WHO 
      • Selection of the comparator product based on previous policies/practices in Malaysia:- 
        1. A generic product that has been used in a bioequivalence study with the original comparator (registered with DCA) and the BE study was found to be satisfactory (fulfilled all requirements). The said generic product may be selected as a new comparator or an additional comparator.

    LIST B

    Generic products containing drug substances/API(s) listed in List B are granted biowaiver due to unavailability/ inaccessibility of comparator/innovator product:

    The applicant/product registration holder will have to submit the following data to demonstrate and prove consistency between batches in place of bioequivalence report:
    1. Process Validation Report (PV) for 3 consecutive batches
    2. Comparative Dissolution Profile (CDP) for 3 consecutive batches that should fulfill the ASEAN guidelines/requirements for carrying out/conducting the CDP
    However, NPRA reserves the rights to request for additional information/data from the applicant/ Product Registration Holder that has been granted a biowaiver for proof of efficacy when there is a product complaint pertaining to its efficacy.

    List B is not exhaustive and will be reviewed from time to time if and when there are any issues on sourcing for the comparator/innovator product.



    III. Other Considerations

    LIST C

    1. Nystatin

    Bioequivalence study can be waived for a generic product containing nystatin due to local effect and no significant systemic absorption. However, in-vitro comparative dissolution profile (CDP) study between the test and reference product need to be conducted to prove similarity.

    (Decision: National Working Committee for BE Studies Meeting 1/2013 – 13th March 2013)

    2. Sevelamer Carbonate

    Bioequivalence study is not required for a generic product containing sevelamer carbonate due to local effect. However, the following studies are required to support the interchangeability between the test and comparator product:-
    1. In-Vitro Equilibrium Binding Study
    2. In-Vitro Kinetic Binding Study
    (Decision: Regulatory Policy Meeting 1/2013 - 20th March 2013)

    3. Phentermine Hydrochloride

    Bioequivalence study is not required for all generic products containing Phentermine Hydrochloride. This is because generic products containing phentermine hydrochloride (not of the resin/ion resin complex form) posses drug release specifications as specified in the United States Pharmacopeia (USP), which is not similar to drug release specifications of the innovator/comparator product that contains a phentermine resin/ion resin complex. However, the label on these generic products must include the following statement:-
    ‘Not Interchangeable with Duromine and other brand of product containing Phentermine Resin’.

    (Decision: National Working Committee for BE Studies Meeting 1/2013- 13th March 2013)

    4. Phenytoin Sodium
    1. For Generic immediate release, oral solid dosage form product which follows USP/BP specification and bioequivalence study is not conducted, the label need to state ‘Not interchangeable with Dilantin and other brands of product containing Phenytoin’.
    2. For Generic immediate release, oral solid dosage form product which performed BE study and found bioequivalent with Innovator product (Dilantin), there is no requirement to include the statement no. (i).
    (Decision: National Working Committee for BE Studies Meeting 1/2010 – 8th December 2010)

    5. Gliclazide
    1. Gliclazide remain in BE list requirement.
    2. For Generic immediate release, oral solid dosage form product which follows BP specification and bioequivalence study is not conducted, the label need to state ‘The dose may need to be titrated if patient has been switched from a different brand of product containing Gliclazide’.
    3. For Generic immediate release, oral solid dosage form product which does not follow BP specification and bioequivalence study is also not conducted, the label need to include statement no. (ii).
    4. For Generic immediate release, oral solid dosage form product which performed BE study and found bioequivalent with Innovator product (Diamicron), there is no requirement to include the statement no. (ii).
    (Decision: National Working Committee for BE Studies Meeting 1/2009–19th August 2009)

    6. Mefenamic Acid

    Bioequivalence study is not required for all generic products containing Mefenamic Acid. However, the applicant/product registration holder will have to submit the following data to demonstrate and prove consistency between batches in place of bioequivalence report:
    1. Process Validation Report (PV) for 3 consecutive batches
    2. Comparative Dissolution Profile (CDP) for 3 consecutive batches that should fulfill the ASEAN guidelines/requirements for carrying out/conducting the CPD
    (Decision: National Working Committee for BE Studies Meeting 1/2014 – 23th April 2014)

    7. Chlorpheniramine Maleate

    Bioequivalence study is not required for all generic products containing
    1. Chlorpheniramine Maleate
    2. Chlorpheniramine Maleate + Paracetamol
    3. Chlorpheniramine Maleate + Phenylephrine HCl
    4. Chlorpheniramine Maleate + Phenylephrine HCl + Paracetamol
    5. Chlorpheniramine Maleate + Pseudoephedrine HCl + Paracetamol

    However, the applicant/product registration holder will have to submit the following data to demonstrate and prove consistency between batches in place of bioequivalence report:

    1. Process Validation Report (PV) for 3 consecutive batches
    2. Comparative Dissolution Profile (CDP) for 3 consecutive batches that should fulfill the ASEAN guidelines/requirements for carrying out/conducting the CDP

    (Decision: National Working Committee for BE Studies Meeting 3/2015 – 9th December 2015)

    8. Dexchlorpheniramine Maleate

    Bioequivalence study is not required for all generic products containing:-
    1. Dexchlorpheniramine Maleate
    2. Dexchlorpheniramine Maleate + Pseudoephedrine HCl
    3. Dexchlorpheniramine Maleate + Pseudoephedrine HCl + Paracetamol

    However, the applicant/product registration holder will have to submit the following data to demonstrate and prove consistency between batches in place of bioequivalence report:

    1. Process Validation Report (PV) for 3 consecutive batches
    2. Comparative Dissolution Profile (CDP) for 3 consecutive batches that should fulfill the ASEAN guidelines/requirements for carrying out/conducting the CDP

    (Decision: National Working Committee for BE Studies Meeting 3/2015 – 9th December 2015)

    9. Orphenadrine Citrate

    1. For generic immediate release, oral solid dosage form product which bioequivalence study is not conducted, the label need to state ‘Not interchangeable with Noflex and other brand of product containing orphenadrine citrate’.
    2. For Generic immediate release, oral solid dosage form product which performed BE study and found bioequivalent with Innovator product (Norflex), there is no requirement to include the statement no. (ii).

      (Decision: National Working Committee for BE Studies Meeting 1/2016 – 16th Jun 2016)

    10. Dextromethorphan Hydrobromide

    Bioequivalence study is not required for all generic products containing:-

       i) Dextromethorphan HBr + Phenylephedrine HCl + Paracetamol
      ii) Dextromethorphan HBr + Pseudoephedrine HCl + Paracetamol

    However, the applicant/product registration holder will have to submit the following data to demonstrate and prove consistency between batches in place of bioequivalence report:

      a. Process Validation Report (PV) for 3 consecutive batches

      b. Comparative Dissolution Profile (CDP) for 3 consecutive batches that should fulfill the ASEAN guidelines/requirements for carrying out/conducting the CDP

    (Decision: National Working Committee for BE Studies Meeting 2/2017 – 27th September 2017)

qrcode