I. Biowaiver considerations based on unavailability/inaccessibility of comparator product

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

The Drug Control Authority (DCA) at its 171st meeting (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 Drug Control Authority (DCA) at its 271st meeting (16th December 2013) approved the proposal that generic product may be considered for biowaiver if it fulfilled ALL of the following criteria:

1. The comparator 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bioequivalence studies that is before 1999 and the registration status of the said comparator product is either cancel, withdrawn, terminated or expired
2. The comparator 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. 

Generic products containing drug substances/ API(s) listed below are considered for biowaiver due to unavailability/inaccessibility of comparator product:

• 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 
• Dicyclomine HCl
• Dimenhydrinate 
• Diphenhydramine HCl + Paracetamol
• Diphenoxylate HCl+ Atropine Sulphate
• Dipyridamole
• Ephedrine HCl + Theophylline
• Erythromycin Stearate 
• Ethambutol
• Flucloxacillin
• Fludrocortisone Acetate
• Imipramine HCl
• Lithium Carbonate 
• L-Tryptophan
• 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

The 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 fulfil the ASEAN guidelines/requirements for conducting the CDP

However, NPRA reserves the rights to request for additional information/data from the Product Registration Holder that has been considered for biowaiver for proof of efficacy when there is a product complaint pertaining to its efficacy.

The drug substance/API listed above is not exhaustive and will be reviewed from time to time if and when there are any issues on sourcing for the comparator product.

 

II. Other Considerations

Generic products containing drug substances/ API(s) listed below are considered for biowaiver due to other considerations.

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) possess 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 needs to include the statement ‘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 in (a).

(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 needs to include the statement ‘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 needs to include statement in (b).
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 in (b).

(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 fulfil the ASEAN guidelines/requirements for 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 fulfil the ASEAN guidelines/requirements for 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 fulfil the ASEAN guidelines/requirements for 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 needs to include the statement ‘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 in (a).

(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:-

1. Dextromethorphan HBr + Phenylephedrine HCl + Paracetamol
2. 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:

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

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