Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1
(1997; 248 pages) [French] View the PDF document
Table of Contents
Open this folder and view contentsIntroduction
Open this folder and view contents1. National drug regulation
Close this folder2. Product assessment and registration
View the documentGuidelines for the assessment of herbal medicines1,2
Open this folder and view contentsStability of drug dosage forms1
Open this folder and view contentsGuidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms1
Close this folderMultisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability1
View the documentIntroduction
View the documentGlossary
Open this folder and view contentsPart One. Regulatory assessment of interchangeable multisource pharmaceutical products
Open this folder and view contentsPart Two. Equivalence studies needed for marketing authorization
Open this folder and view contentsPart Three. Tests for equivalence
View the documentPart Four. In vitro dissolution tests in product development and quality control
View the documentPart Five. Clinically important variations in bioavailability leading to non-approval of the product
View the documentPart Six. Studies needed to support new post-marketing manufacturing conditions
View the documentPart Seven. Choice of reference product
View the documentAuthors
View the documentReferences
View the documentAppendix 1. Examples of national requirements for in vivo equivalence studies for drugs included in the WHO Model List of Essential Drugs (Canada, Germany and the USA, December 1994)
View the documentAppendix 2. Explanation of symbols used in the design of bioequivalence studies in humans, and commonly used pharmacokinetic abbreviations
View the documentAppendix 3. Technical aspects of bioequivalence statistics
Open this folder and view contents3. Distribution
Open this folder and view contents4. The international pharmacopoeia and related activities
Open this folder and view contents5. Basic tests
Open this folder and view contents6. Laboratory services
Open this folder and view contents7. International trade in pharmaceuticals
Open this folder and view contents8. Counterfeit products
Open this folder and view contents9. Training
View the documentSelected WHO publications of related interest
View the documentBack cover
 

Appendix 1. Examples of national requirements for in vivo equivalence studies for drugs included in the WHO Model List of Essential Drugs (Canada, Germany and the USA, December 1994)

General

National requirements for equivalence studies for specific drug products differ from country to country. National requirements for equivalence studies of a specific drug product can be based on any of the following:

- case-by-case study;
- criteria established by a national advisory committee; or
- application of the national regulatory guidelines.

A list of examples is presented in Table 1. It is intended to be illustrative only, in accordance with the guidelines, and does not represent a formal recommendation.

The list is based on substances and products included in the WHO Model List of Essential Drugs (1), but only includes essential drugs for which in vivo studies are required because of the nature of the dosage form. Some dosage forms, e.g. solutions and injections, have therefore been omitted from the list as they have not been identified as requiring studies in one of the three countries covered.

Examples of decisions on criteria taken by national authorities

Canada

At present, demonstration of bioequivalence is required for those drugs which are not considered to have been marketed in Canada for their intended purpose(s) for sufficient time and in sufficient quantity to establish safety and efficacy (new drugs). Bioequivalence may be demonstrated by comparative bioequivalence studies or by clinical studies including, where applicable, acceptable surrogate models. Scientific criteria, similar to those of the European Community and Australia, are being developed for deciding in which situations in vivo demonstration of bioequivalence is required for drugs that are not new.

Germany

Over the past years, the National Advisory Committee has taken the decision on the need for a comparative bioavailability/bioequivalence study as a requirement for marketing authorization. These decisions have been based on published data for the drug substance and its dosage form, and on the use of an algorithm. Details of the algorithm, the criteria and the resulting decisions have been published in the German Federal Register. In certain circumstances, the regulatory authority takes decisions on a case-by-case basis.

USA

Drug products introduced before 1938 in the USA do not require approval for marketing and therefore no in vivo equivalence study is needed. The majority of drug products, other than solution dosage forms, approved between 1938 and 1962, and known to have potential bioavailability problems, require in vivo equivalence studies. Generally, drug products approved after 1962, with the exception of solution dosage forms, also require in vivo equivalence studies.

Table 1. Examples of national requirements for equivalence studies1

1 +: in vivo studies required; +b: bioequivalence studies; +p: pharmacodynamic studies: +c: clinical trials; -: no in vivo studies required; ?: decision on the type of in vivo studies pending; O: no information available, no final decision taken, or not available on national market.

Drug substance

Dosage form

Canada

Germany

USA

acetazolamide

tablet, 250 mg

+b

+b

+b

acetylsalicylic acid

suppository, 50-150 mg

?

+b

-

 

tablet, 100-500 mg

-

+b

-

albendazole

tablet, 200 mg

o

+b

o

allopurinol

tablet, 100 mg

+b

+b

+b

aluminium hydroxide

oral suspension, 320 mg/5 ml

-

+p

-

 

tablet, 500 mg

-

+p

-

amiloride hydrochloride

tablet, 5 mg

+b

-

+b

aminobenzoic acid

cream

?

+p+c

-

 

gel

?

+p+c

-

 

lotion

?

+p+c

-

aminophylline

tablet, 100 mg, 200 mg

?

o

+b

amitriptyline hydrochloride

tablet, 25 mg

?

+b

+b

amoxicillin

capsule, 250 mg, 500 mg

+b

+b

+b

 

powder for oral suspension, 125 mg/5 ml

+b

+b

+b

 

tablet, 250 mg, 500 mg

+b

+b

+b

ascorbic acid

tablet, 50 mg

-

?

-

atenolol

tablet, 50 mg, 100 mg

+b

-

+b

atropine sulfate

solution (eye drops), 0.1%, 0.5%, 1%

o

+c

-

 

tablet, 1 mg

o

?

o

azathioprine

tablet, 50 mg

+b

+b

+b

bacitracin zinc

ointment, 500 IU + neomycin sulfate, 5 mg/g

o

+c

-

beclometasone dipropionate

inhalation, 50 µg/dose

?

+p+c

+p

benzathine benzylpenicillin

powder for injection, 1.44 g of benzylpenicillin (= 2.4 million ID) in 5-ml vials

o

-

+b

benznidazole

tablet, 100 mg

o

+b

o

benzoic acid

cream, 6% + salicylic acid, 3%

-

+p+c

o

 

ointment, 6% + salicylic acid, 3%

-

+p+c

-

benzoyl peroxide

cream, 5%

-

+p+c

-

 

lotion, 5%

-

+p+c

-

benzyl benzoate

lotion, 25%

-

+p+c

o

betamethasone valerate

cream, 0.1% of betamethasone

+p

+p+c

+p

 

ointment, 0.1% of betamethasone

+p

+p+c

+p

biperiden hydrochloride

tablet, 2 mg

+b

+b

+b

calamine

lotion

-

+p+c

-

calcium folinate

tablet, 15 mg

+b

o

+b

captopril

tablet, 25 mg

+b

-

+b

carbamazepine

tablet, 100 mg, 200 mg

+b

+b

+b

carbidopa

tablet, 10 mg + levodopa, 100 mg

+b

+b

+b

 

25 mg + levodopa, 250 mg

+b

+b

+b

chloramphenicol

capsule, 250 mg

?

+b

+b

chloramphenicol palmitate

oral suspension, 150 mg of chloramphenicol/5 ml

?

+b

+b

chloramphenicol sodium succinate

oily suspension, injection, 0.5 g of chloramphenicol/ml in 2-ml ampoule

o

+b

o

chloroquine hydrochloride

injection, 40 mg of chloroquine/ml in 5-ml ampoule

o

-

-

chloroquine phosphate

tablet, 150 mg of chloroquine

o

+b

-

chloroquine sulfate

tablet, 150 mg of chloroquine

o

+b

o

chlorphenamine hydrogen maleate

tablet, 4 mg

-

?

-

chlorpromazine hydrochloride

tablet, 100 mg

?

+b

+b

ciclosporin

capsule, 25 mg

+b

+b

+b

cimetidine

tablet, 200 mg

+b

-

+b

ciprofloxacin hydrochloride

tablet, 250 mg of ciprofloxacin

+b

+b

+b

clofazimine

capsule, 50 mg, 100 mg

o

+b

+b

clomifene citrate

tablet, 50 mg

+b

+b

+b

clomipramine hydrochloride

capsule, 10 mg, 25 mg

+b

o

+b

cloxacillin sodium

capsule, 500 mg of cloxacillin

?

+b

+b

codeine phosphate

tablet, 10 mg, 30 mg

o

-

-

colchicine

tablet, 500 µg

?

+b

-

cyclophosphamide

tablet, 25 mg

+b

+b

+b

dapsone

tablet, 50 mg, 100 mg

?

+b

+b

desmopressin acetate

nasal spray, 10 µg/metered dose

+b+p

+p+c

?

dexamethasone

tablet, 500 µg, 4 mg

?

?

+b

diazepam

scored tablet, 2 mg, 5 mg

+b

-

+b

diethylcarbamazine dihydrogen citrate

tablet, 50 mg

o

+b

+b

digitoxin

tablet, 50 µg, 100 µg

?

+b

-

digoxin

tablet, 62.5 µg, 250 µg

?

+b

-

diloxanide furoate

tablet, 500 µg

o

+b

o

dimercaprol

injection, in oil, 50 mg/ml in 2-ml ampoule

+b+c

+b1

-

dioxybenzone

cream

?

+p+c

o

 

lotion

?

+p+c

o

 

gel

?

+p+c

o

dithranol

ointment, 0.1-2%

-

+p+c

-

doxycycline hyclate

capsule, 100 mg of doxycycline

+b

+b

+b

 

tablet, 100 mg of doxycycline

+b

+b

+b

ergocalciferol

capsule, 1.25 mg (50 000 IU)

o

+b

-

 

tablet, 1.25 mg (50 000 IU)

o

+b

-

ergometrine hydrogen maleate

tablet, 200 µg

?

+b

-

ergotamine tartrate

tablet, 2 mg

o

+b

-

erythromycin ethylsuccinate

capsule, 250 mg of erythromycin

?

+b

+b

 

powder for oral suspension, 125 mg of

?

+b

+b

 

erythromycin tablet, 250 mg of erythromycin

?

+b

+b

erythromycin stearate

capsule, 250 mg of erythromycin

?

+b

+b

 

powder for oral suspension, 125 mg of

?

+b

+b

 

erythromycin tablet, 250 mg of erythromycin

?

+b

+b

ethambutol hydrochloride

tablet, 100-400 mg

+b

+b

+b

ethinylestradiol

tablet, 50 µg

+b

+b

+b

 

tablet, 30 µg + levonorgestrel, 150 µg

+b

+b

+b

 

tablet, 50 µg + levonorgestrel, 250 µg

+b

+b

+b

 

tablet, 35 µg + norethisterone, 1.0 mg

+b

+b

+b

ethosuximide

capsule, 250 mg

?

+b

+b

etoposide

capsule, 100 mg

+b

+b

+b

ferrous sulfate

tablet, 60 mg of Fe

-

o

-

 

tablet, 60 mg of Fe + folic acid, 250 µg

-

o

-

flucytosine

capsule, 250 mg

+b

+b

+b

fludrocortisone acetate

tablet, 100 µg

+b

+b

+b

fluorouracil

ointment, 5%

+c

+p+c

?

fluphenazine decanoate

injection, 25 mg in 1-ml ampoule

?

+b1

-

fluphenazine enantate

injection, 25 mg in 1-ml ampoule

?

+b1

-

folic acid

tablet, 5 mg, 1 mg

+b

+b

-

 

tablet, 250 µg + ferrous sulfate, 60 mg of Fe

-

+b

-

furosemide

tablet, 40 mg

+b

+b

+b

gentamicin sulfate

solution (eye drops), 0.3%

+c

+p+c

-

glyceryl trinitrate

tablet (sublingual), 500 µg

?

+b

-

griseofulvin

capsule, 125 mg, 250 mg

?

+b

+b

 

tablet, 125 mg, 250 mg

?

+b

+b

haloperidol

tablet, 2 mg, 5 mg

+b

-

+b

hydralazine hydrochloride

tablet, 25 mg, 50 mg

o

+b

-

hydrochlorothiazide

tablet, 25 mg, 50 mg

?

-

+b

hydrocortisone acetate

cream, 1%

o

+p+c

-

 

ointment, 1%

o

+p+c

-

 

suppository, 25 mg

o

+p+c

?

ibuprofen

tablet, 200 mg

+b

-

+b

idoxuridine

eye ointment, 0.2%

o

+p+c

+c

 

solution (eye drops) 0.1%

o

-

-

indometacin

capsule, 25 mg

+b

-

+b

 

tablet, 25 mg

+b

-

o

insulin: insulin (soluble)

injection, 40 IU/ml in 10-ml vial,

+b

-

+b+p

 

80 IU/ml in 10-ml vial,

+b

-

+b+p

 

100 IU/ml in 10-ml vial

+b

-

+b+p

insulin zinc suspension

injection, 40 IU of insulin/ml in 10-ml vial

+b

o

+b+p

 

80 IU of insulin/ml in 10-ml vial

+b

o

+b+p

insulin (intermediate- acting)

100 IU of insulin/ml in 10-ml vial

+b

-

+b+p

isophane insulin

injection, 40 IU of insulin/ml in 10-ml vial

+b

+b

+b+p

 

80 IU of insulin/ml in 10-ml vial

+b

+b

+b+p

 

100 IU of insulin/ml in 10-ml vial

+b

+b

+b+p

iodized oil

capsule, 200 mg

?

o

o

iopanoic acid

tablet, 500 mg

o

o

-

iron dextran

injection, 50 mg of Fe/ml in 2-ml ampoule

+c

-

+b+p

isoniazid

tablet, 100-300 mg

+b

+b

-

 

tablet, 100 mg + rifampicin, 150 mg

o

+b

+b

 

tablet, 150 mg + rifampicin, 300 mg

o

+b

+b

 

tablet, 100 mg + thioacetazone, 50 mg

o

+b

o

 

tablet, 300 mg + thioacetazone, 150 mg

 

+b

o

isosorbide dinitrate

tablet (sublingual), 5 mg

+b

+b

+b

ivermectin

scored tablet, 6 mg

o

+b

o

ketoconazole

oral suspension, 100 mg/5 ml

+b

+b

+b

 

tablet, 200 mg

+b

+b

+b

levamisole hydrochloride

tablet, 50 mg, 150 mg

+b

+b

+b

levodopa

tablet, 100 mg + carbidopa, 10 mg

+b

+b

+b

 

250 mg + carbidopa, 25 mg

+b

+b

+b

levonorgestrel

tablet, 150 µg + ethinylestradiol, 30 µg

+b

+b

+b

 

tablet, 250 µg + ethinylestradiol, 50 µg

+b

+b

+b

levothyroxine sodium

tablet, 50 µg, 100 µg

?

+b

-

lithium carbonate

capsule, 300 mg

+b

+b

+b

 

tablet, 300 mg

+b

+b

+b

mebendazole

chewable tablet, 100 mg

+b

+b

+b+c

medroxyprogesterone acetate (depot)

injection, 150 mg/ml in 1-ml vial,

?

+b

+b

 

injection, 50 mg/ml in 3-ml vial

?

+b

+b

mefloquine hydrochloride

tablet, 250 mg

+b

+b

+b

mercaptopurine

tablet, 50 mg

+c+b

+b

+b

methionine (DL-)

tablet, 250 mg

?

?

-

methotrexate sodium

tablet, 2.5 mg of methotrexate

+b+c

+b

+b

methyldopa

tablet, 250 mg

?

+b

+b

metoclopramide hydrochloride

tablet, 10 mg of metoclopramide

+b

-

+b

metrifonate

tablet, 100 mg

o

+b

o

metronidazole

suppository, 500 mg, 1 g

o

+b

o

 

tablet, 200-500 mg

+b

+b

+b

metronidazole benzoate

oral suspension, 200 mg of metronidazole/5 ml

o

+b

o

mexenone

cream

o

+p+c

o

 

lotion

o

+p+c

o

 

gel

o

+p+c

o

miconazole nitrate

cream, 2%

+c

+p+c

+c

 

ointment, 2%

+c

+p+c

+c

morphine sulfate

tablet, 10 mg

o

+b

-

nalidixic acid

tablet, 500 mg

+b

+b

+b

neomycin sulfate

ointment, 5 mg + bacitracin zinc, 500 IU/g

o

+p+c

-

neostigmine bromide

tablet, 15 mg

?

?

-

niclosamide

chewable tablet, 500 mg

o

+b

+b

nicotinamide

tablet, 50 mg

-

?

-

nifedipine

capsule, 10 mg

+b

+b

+b

 

tablet, 10 mg

+b

+b

o

nifurtimox

tablet, 30 mg, 120 mg, 250 mg

o

+b

o

nitrofurantoin

tablet, 100 mg

?

+b

+b

norethisterone

tablet, 350 µg, 5 mg

+b

+b

o

 

tablet, 1.0 mg + ethinylestradiol, 35 µg

+b

+b

o

norethisterone enantate

oily solution, 200 mg/ml in 1-ml ampoule

?

+b

o

nystatin

lozenge, 100000 IU

+

?

+b

 

tablet, 100 000 IU, 500 000 IU

o

-

-

oxamniquine

capsule, 250 mg

o

+b

+b

oxybenzone

cream

-

+p+c

+c

 

gel

-

+p+c

+c

 

lotion

-

+p+c

+c

paracetamol

suppository, 100 mg

+b

-

o

 

tablet, 100-500 mg

-

-

o

penicillamine

capsule, 250 mg

+b

-

+b

 

tablet, 250 mg

+b

-

+b

permethrin

lotion, 1%

-

+p+c

+c

pethidine hydrochloride

tablet, 50 mg, 100 mg

o

+b

-

phenobarbital

tablet, 15-100 mg

-

o

-

phenoxymethylpenicillin potassium

powder for oral suspension, 250 mg of phenoxymethylpenicillin/5 ml

o

+b

+b

 

tablet, 250 mg of phenoxymethylpenicillin

?

+b

+b

phenytoin sodium

capsule, 25 mg, 100 mg

+b

+b

+b

 

tablet, 25 mg, 100 mg

+b

+b

o

phytomenadione

tablet, 10 mg

+b

o

+b

pilocarpine hydrochloride

solution (eye drops), 2%, 4%

o

+p+c

-

pilocarpine nitrate

solution (eye drops), 2%, 4%

o

+p+c

o

piperazine adipate

tablet, 500 mg of piperazine hydrate

-

o

o

piperazine citrate

tablet, 500 mg of piperazine hydrate

-

o

+b

podophyllum resin

solution, topical, 10-25%

o

+p+c

-

potassium iodide

tablet, 60 mg

-

-

-

praziquantel

tablet, 150 mg, 600 mg

o

+b

+b

prednisolone

solution (eye drops), 0.5%

o

+p+c

o

 

tablet, 1 mg, 5 mg

?

+b

+b

primaquine diphosphate

tablet, 7.5 mg of primaquine, 15 mg of primaquine

?

+b

-

procainamide hydrochloride

tablet, 250 mg, 500 mg

+b

+b

+b

procaine benzylpenicillin

powder for injection, 1 g (= 1 million IU),

?

-

+b

 

3 g (= 3 million IU)

o

 

+b

procarbazine hydrochloride

capsule, 50 mg

+c+b

+b

+b

proguanil hydrochloride

tablet, 100 mg

o

+b

o

promethazine hydrochloride

tablet, 10 mg, 25 mg

?

+b

+b

propranolol hydrochloride

tablet, 10 mg, 20 mg, 40 mg, 80 mg

+b

+b

+b

propyliodone

oily suspension, 500-600 mg/ml in 20-ml ampoule

o

o

-

propylthiouracil

tablet, 50 mg

?

-

+b

pyrantel embonate

oral suspension, 50 mg of pyrantel/ml

o

+b

+b

 

chewable tablet, 250 mg of pyrantel

o

+b

o

pyrazinamide

tablet, 500 mg

+b

+b

+b

pyridostigmine bromide

tablet, 60 mg

+b

?

+b

pyridoxine hydrochloride

tablet, 25 mg

-

?

-

pyrimethamine

tablet, 25 mg + sulfadoxine, 500 mg

+b

+b

+b

quinidine sulfate

tablet, 200 mg

?

+b

+b

quinine bisulfate

tablet, 300 mg of quinine

+b

+b

-

quinine sulfate

tablet, 300 mg of quinine

?

+b

-

reserpine

tablet, 100 µg, 250 µg

?

+b

+b

retinol palmitate

capsule, 200 000 IU (110 mg) of retinol

-

?

o

 

sugar-coated tablet, 10 000 IU of retinol

-

?

o

riboflavin

tablet, 5 mg

-

?

-

rifampicin

capsule, 150 mg, 300 mg

+b

+b

+b

 

tablet, 150 mg, 300 mg

+b

+b

+b

 

tablet, 150 mg + isoniazid, 100 mg

o

+b

+b

 

300 mg + isoniazid, 150 mg

o

+b

+b

salbutamol sulfate

inhalation (aerosol), 100 µg of salbutamol per dose

?,+p

+p+c

+p

 

respirator solution for use in nebulizers, 5 mg/ml

?,+p

+p+c

-

 

tablet, 2 mg, 4 mg of salbutamol

+b

+b

+b

salicylic acid

cream, 3% + benzoic acid, 6%

-

+p+c

o

 

ointment, 3% + benzoic acid, 6%

-

+p+c

-

 

solution, topical, 5%

-

+p+c

o

silver nitrate

solution (eye drops), 1%

o

+p+c

-

silver sulfadiazine

cream, 1% in 500-g container

+c

+p+c

+c

sodium cromoglicate

inhalation, 20 mg/dose

? or +c

+p+c

+p+c

sodium fluoride

tablet, 500 µg

-

-

-

sodium valproate

enteric coated tablet, 200 mg, 500 mg

+b

+b

+b

spironolactone

tablet, 25 mg

+b

+b

+b

sulfadimidine

tablet, 500 mg

o

+b

o

sulfadoxine

tablet, 500 mg + pyrimethamine, 25 mg

+b

+b

+b

sulfamethoxazole

oral suspension 200 mg + trimethoprim, 40 mg/5 ml

+b

+b

+b

 

tablet, 100 mg + trimethoprim, 20 mg

+b

+b

+b

 

400 mg + trimethoprim, 80 mg

+b

+b

+b

sulfasalazine

tablet, 500 mg

+b

+b

+b

tamoxifen citrate

tablet, 10 mg of tamoxifen, 20 mg of tamoxifen

+b

+b

+b

testosterone enantate

injection, 200 mg in 1 ml ampoule

?

+b

-

tetracaine hydrochloride

solution (eye drops), 0.5%

o

+p+c

-

tetracycline hydrochloride

capsule, 250 mg

?

+b

+b

 

tablet, 250 mg

?

+b

+b

 

eye ointment, 1%

?

+p+c

-

thiamine hydrochloride

tablet, 50 mg

-

?

-

thioacetazone

tablet, 50 mg + isoniazid, 100 mg

o

+b

o

 

150 mg + isoniazid, 300 mg

o

+b

o

tolbutamide

tablet, 500 mg

+b

+b

+b

trimethoprim

oral suspension, 40 mg + sulfamethoxazole, 200 mg/5 ml

+b

+b

+b

 

tablet, 100 mg, 200 mg

+b

+b

+b

 

tablet, 20 mg + sulfamethoxazole, 100 mg

+b

+b

+b

 

80 mg + sulfamethoxazole, 400 mg

+b

+b

+b

tropicamide

solution (eye drops), 0.5%

o

+p+c

-

verapamil hydrochloride

tablet, 40 mg, 80 mg

+b

+b

+b

warfarin sodium

tablet, 1 mg, 2 mg, 5 mg

?

+b

+b

zinc oxide

cream

-

+p+c

-

 

ointment

-

+p+c

-

1 “Depot” preparation for injection.

Reference

1. The use of essential drugs. Sixth report of the WHO Expert Committee. Geneva, World Health Organization, 1995 (WHO Technical Report Series, No. 850).

to previous section
to next section
 
 
The WHO Essential Medicines and Health Products Information Portal was designed and is maintained by Human Info NGO. Last updated: November 5, 2014