Basis for BCS-based Biowaiver

Prepared by:Mohamed AbdeenR&D department

Azal pharmaceutical Co.LTD

In 1995 the American Department of Health and Human Services, US Food and Drug Administration (HHS-FDA) instigated the Biopharmaceutics Classifi cation System (BCS) for:

scale-up and post-approval changes (SUPAC)

According to the HHS-FDA defi nitions,four possible categories for an API according to the BCS are: Class I◦ High Solubility◦ High Permeability

Class II◦ Low Solubility◦ High Permeability

Class III◦ High Solubility◦ Low Permeability

Class IV◦ Low Solubility◦ Low Permeability

the highest single dose is completely soluble in 250 ml or less of aqueous solution at pH 1 - 6.8 (37 °C)

♦ highest dose recommended by WHO (as recommended in the WHO Model List of Essential Medicines)

or

♦ highest dose strength (if not listed s.o.)

250 ml: derived from typical BE study protocols that prescribe the administration of a drug product to fasting human volunteers with a glass (approximately 250 ml) water.

If the highest orally administered dose can be completely dissolved in this amount of water, independent of the physiological pH value (hence the determination over the pH range 1–7.5), solubility problems are not expected to hinder the uptake of the API in the small intestine.

♦ Revised EMA guidance: extent of absorption ≥ 85 % (absolute BA or mass balance data) or ‘known absorption’

♦ FDA guidance: absolute BA >90 %

♦ WHO guidance: extent of absorption at least 85 % in human

site fasted pH fed pH

stomach 1.4 – 2.1 4.3 – 5.4

small intestine: duodenum 4.9 – 6.4 4.2 – 6.1 jejunum 4.4 – 6.6 5.2 – 6.2 ileum 6.5 – 7.4 6.8 – 7.5

large intestine: cecum upper colon lower colon

6.46.07.5

♦ PK-studies (e.g. absolute BA or mass-balance studies)

♦ Human intestinal perfusion studies♦ Animal models♦ Caco 2 cell lines or other suitable, validated

cell lines(in-situ or in-vitro models for passively transported APIs only)

As the BCS is only applicable to APIs which are absorbed from the small intestine; drugs absorbed from other sites (e.g. from the oral cavity) are not eligible for a biowaiver.

• if two products, containing the same drug, have the same concentration-time profile at the intestinal membrane surface then they will have the same rate and extent of absorption

• same in vivo dissolution profile under all luminal conditions

formulation components do not effect the membrane permeability and/or intestinal transit

dissolutiondrug product drug substance in solution

membrane transport drug substance in the system

Dissolution, solubility, and intestinal permeability are the three major factors that govern the rate and extent of absorption of a drug that is stable in the GI tract.

Solubility (Drug) High solubility- ensure that solubility

is not likely to limit dissolution and,

therefore, absorption

Dissolution(Product)

Very rapid/rapid dissolution - ensure that

in vivo dissolution is not likely to be the

“rate determining” step

Permeability(Drug)

High permeability - ensure that drug

is completely absorbed during the limited

transit time through the small intestine

An IR drug product is considered VERY RAPIDLY DISSOLVING when >85% of the labeled amount of drug substance dissolves within 15 minutes.

Rapid dissolution:An IR drug product is considered RAPIDLY DISSOLVING

when >85% of the labeled amount of drug substance

dissolves within 30 minutes.

.....is defined as

in vitro instead of in vivo ‘bioequivalence’ testing

comparison of test and reference”BCS-based biowaivers are intended only for

bioequivalence studies. They do not apply to

food effect bioavailability studies or other

pharmacokinetic studies.”

should contain a Class I API(now extent to class II);

should be rapidly dissolving, meaning it should release at least 85% of its content in 30 minutes in three different media (pH 1.2, pH 4.5 and pH 6.8, composition see “Multisource document”)1 in a paddle (50 rpm) or basket (100 rpm) apparatus at 37 °C and a volume of 900 ml;

should not contain excipients which could infl uencethe absorption of theAPI;

should not contain an API with a narrow therapeutic index; and

should not be designed to be absorbed from the oral cavity.

The reasoning for the above-mentioned dissolution restrictions is that when a highly soluble, highly permeable API dissolves rapidly, it behaves like a solution in the gastrointestinal tract. If this is the case, the pharmaceutical composition of the product is insignificant, provided that excipient which influence the uptake across the gut wall are excluded from the formulation.

some excipients can influence motility and/or permeability in the gastrointestinal tract( eg: mannitol, sorpitol, SLS , etc …)

If the multisource product under consideration contains excipients that have been used before in similar amounts in other formulations of the same API, it can be reasonably concluded that these excipients will have no unexpected consequences for the bioavailability of the product. If, however, the formulation contains different excipients, or amounts of the same excipients that are very different from usual, the national authority may choose to declare the biowaiver procedure inapplicable.

a. according to HHS-FDA

CLASS I

Eligible

CLASS II

Not eligible

CLASS III

Not eligible

CLASS IV

Not eligible

CLASS I

Eligible

CLASS II

Eligible only if the D:S is 250 ml or lower at pH 6.8

CLASS III

Eligible if very rapidly dissolving

CLASS IV

Not eligible

For BCS class I :In vitro comparison of immediate release oral

drug products (T and R):first option: very rapidly dissolving products;

Not less than 85 % of labeled amount (12 dosage form)are dissolved within 15 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm – no further profile comparison of T and R is required.

reasonable, validated experimental conditions/methods are strongly recommended!

Not less than 85 % of labeled amount(12 dosage form) are dissolved within 30 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm

Proving similarity of dissolution profiles of T and R e.g., using f2-test, unless similarity is obvious.

f2=50 x log {[ 1 + (1/n) t=1n (Rt – Tt)2 ]-0.5 x 100

„identical“ profiles: f2 =100

„similar“ profiles: f2 between 50 and 100

Two dissolution profiles are considered similar when the f2 value is $50. To allow the use of mean data, the coefficient of variation should not be more than 20% at the earlier time points (e.g., 10 minutes), and should not be more than 10% at other time points. Note that when both test and reference products dissolve 85% or more of the label amount of the drug in #15 minutes using all three dissolution media recommended above, the profile comparison with an f2 test is unnecessary.

very rapidly dissolving products; Not less than 85 % of labeled amount (12 dosage form)are dissolved within 15 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm.

Generally, the risks of an inappropriate biowaiver decision should be more critically reviewed (e.g. site-specifi c absorption, induction/competition at the absorption site, excipient composition and therapeutic risks) for products containing BCS Class III APIs than for BCS Class I drugs.

These are eligible for a biowaiver provided that the multisource product:

is rapidly dissolving, i.e. 85% or more dissolution of the labelled amount of the API should be achieved within 30 minutes in standard media at pH 6.8 using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm; and

• the multisource product exhibits similar dissolution profi les, as determined with the f2 value or equivalent statistical evaluation, to those of the comparator product in buffers at all three pH values (pH 1.2, 4.5 and 6.8).

For multisource products containing BCS Class II APIs with dose:solubility ratios of 250 ml or less, at pH 6.8, the excipients should also be critically evaluated in terms of type and amounts of surfactants in the formulation.

1. Annex 8 Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms(2006)

2. WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010.