Biowaivers

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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)

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