European Journal of Pharmaceutical Sciences 9 (1999) 117–121

www.elsevier.nl / locate / ejps

Commentary

The biopharmaceutics classification system (BCS): Class III drugs —

better candidates for BA / BE waiver?
Henning H. Blume*, Barbara S. Schug
SocraTec R& D, Feldbergstrasse 59, 61440 Oberursel, Germany
Received 16 August 1999; received in revised form 12 October 1999; accepted 12 October 1999

Abstract

Current guidelines (CPMP Note for Guidance in Europe and FDA Guidance for Industry in the USA) consider a waiver of
bioavailability / bioequivalence studies for immediate release dosage forms of highly soluble, highly permeable drug substances (Class I
according to the BCS). In this paper, a waiver of BA / BE studies is being proposed also for Class III compounds (high solubility and low
permeability) in fast dissolving products without excipients which may modify gastro-intestinal transit or membrane permeation. This
type of drug substance may be an even better candidate for a waiver as, in this case, bioavailability will not so much depend on the
formulation characteristics, as on drug substance properties (e.g. permeability).  1999 Published by Elsevier Science B.V. All rights
reserved.

Keywords: Biopharmaceutics classification system; Bioavailability waiver; Class-III drugs; Dissolution; Solubility; Permeability

The discussion of the necessity of bioavailability / bio- • the drug substance has certain properties, e.g.
equivalence (BA / BE) studies in the regulatory process has is not a drug with a narrow therapeutic index,
been one of the major topics of the international debate on exhibits a linear pharmacokinetics and a first pass effect
BA / BE issues during recent years. Two guidelines with less than 70%,
new regulations in this respect were issued recently: the is highly water soluble over the entire physiological pH
CPMP Note for Guidance on the Investigation of Bioavail- range (1–8) at 378C,
ability and Bioequivalence (CPMP, 1998) in Europe, and is highly permeable in the intestine (i.e. extent of
in the USA, the FDA Guidance for Industry ‘‘Waiver of In absorption is greater than 80%)
Vivo Bioavailability and Bioequivalence Studies for Im-
mediate Release Solid Oral Dosage Forms Containing and
Certain Active Moieties /Active Ingredients Based on a
Biopharmaceutics Classification System’’ (FDA, 1999).
• the drug product exhibits a particular quality pattern,
e.g.
excipients have no significant impact on the phar-
1. International regulatory requirements
macokinetics of the active substance(s),
release of the active substance is fast in buffers over the
1.1. European regulations
entire physiological pH range (pH 1–8) at 378C.
According to the CPMP Guideline, bioequivalence
studies should be performed for all generic immediate If all these requirements are met by a certain generic
release products intended for systemic action. However, medicinal product, in vitro dissolution data are considered
exceptions are possible if the following catalogue of sufficient to ensure bioequivalence. For this purpose,
criteria are fulfilled: dissolution profiles have to be ‘‘similar’’ to those of the
reference product. Similarity has to be assessed over the
*Corresponding author. Tel.: 149-6172-458361; fax: 149-6172- entire physiological pH range (e.g. at pH 1.3, 4.6 and 6.8)
489258. by comparing the dissolution curves by means of the f 2
E-mail address: [email protected] (H.H. Blume) equation (FDA, 1997).

0928-0987 / 99 / $ – see front matter  1999 Published by Elsevier Science B.V. All rights reserved.
PII: S0928-0987( 99 )00076-7
118 H.H. Blume, B.S. Schug / European Journal of Pharmaceutical Sciences 9 (1999) 117 – 121

1.2. US regulations of BA / BE studies are based on the Biopharmaceutics

Classification System (BCS) which was developed over
Similar, although more specific requirements are given the last few years. The BCS classifies drug substances in
by the FDA Guidance for Industry. This document is also four groups (Fig. 1) according to their solubility and
only relevant for oral immediate release dosage forms permeability properties (Amidon et al., 1995).
intended for systemic use. According to this guideline The background of this classification is the understand-
‘‘drugs that are poorly permeable, poorly soluble and / or ing that dissolution from the dosage form depends con-
formulated in slowly dissolving dosage forms may be siderably on the solubility of the drug ingredient and that
considered to be drugs with actual or potential bioequival- absorption from the GI tract is dependent on permeability
ence problems’’. As a consequence, in vivo studies are properties of the drug substance. However, dissolution is
requested for such drug products. also affected by the biopharmaceutical characteristics of
In more specific terms, waiver of in vivo studies may be the formulation and absorption from the intestine may be
requested by the sponsor if influenced by certain ingredients (e.g. those modifying GI
transit or membrane permeability).
• the drug substance is highly soluble and highly perme- Consequently, additional requirements on dissolution
able, behaviour were introduced into the system. Thus, a waiver
• the drug product dissolves rapidly, i.e. .85% / 30 min of bioavailability studies may only be granted for products
over the entire physiological pH range (e.g. at pH 1.3, whereby more than 85% of the drug ingredient is dissolved
4.6 and 6.8) and in 30 min in all physiological media. Moreover, in cases of
• the drug is not a drug with a narrow therapeutic index. generic products, waiver of bioequivalence investigations
are only possible if both (test and reference) products
Moreover, stability of the active substance in the exhibit similar dissolution profiles.
medium of the gastrointestinal tract has to be assured
(.95% / 3 h). This supposition is important for the appro-
priate interpretation of experimental findings from solu- 2.2. What is the rate limiting process for
bility and permeability investigations or the mass balance bioavailability?
analysis.
Special attention should be paid to the excipients. They The general understanding behind this concept is that
should be ‘‘well established’’ (i.e. already used in ap- differences in bioavailability (rate and extent) may only be
proved IR forms) and ‘‘unproblematic’’. Excipients are observed between two essentially similar (generic) prod-
considered critical in this respect if they significantly affect ucts if both dosage forms exhibit a different dissolution
behaviour in vivo. However, this statement is only valid as
• dissolution of the active drug ingredient from the long as the release from the dosage form represents the
dosage form (e.g. surfactants), rate controlling process for drug absorption. On the other
• permeation through the intestinal membrane (e.g. en- hand, if the permeation through the intestinal membrane is
hancers), rate limiting, dissolution properties may be of negligible
• gastro-intestinal transit time or importance.
• drug metabolism in the mucosa. This interrelation is elucidated by the following exam-
ples (Figs. 2 and 3).
For glibenclamide generics from the German market,
2. The biopharmaceutics classification system significant differences in dissolution were determined by
use of an appropriately discriminating in vitro method
2.1. General concept (Fig. 2). This observation correlates with the in vivo
findings. Products with a faster release of the active drug
The regulations of both guidelines concerning a waiver ingredient were also absorbed more rapidly in vivo. Thus,

Fig. 1. Classification of drug substances according to the BCS.

 H.H. Blume, B.S. Schug / European Journal of Pharmaceutical Sciences 9 (1999) 117 – 121 119

Fig. 2. In vitro dissolution (left graph, mean curves, n56) and mean plasma profiles (right graph, n57) of six glibenclamide generic products of the
German market (Blume et al., 1984; Blume et al., 1985).

in this case, bioavailability is ‘‘controlled’’ by the release drug substance is released from the dosage form very
of the compound from the dosage form. rapidly in vivo, gastric emptying will become the rate
Significant deviations in rate and extent of dissolution limiting process for drug absorption. In such cases, physi-
were also detected by use of the USP method for two ology, rather than the biopharmaceutical properties of the
controlled / modified release (C / MR) indometacine prod- medicinal product, will be the decisive factor for bioavail-
ucts from the German market. However, such differences ability. Thus, bioavailability is not dependent on the
were not observed between these dosage forms when product performance and consequently in vivo investiga-
investigated in vivo. Bioavailability of both products was tions may be waived.
similar and thus, bioequivalence could be assessed. In this
particular case, bioavailability was not greatly affected by
the release of the active drug ingredient from the dosage 2.4. Bioavailability of class III drugs
form and consequently, rate and extent of absorption was
dependent primarily on the permeation properties of the Compounds classified as Class III drugs are also char-
drug substance through the gut wall membrane. acterised by high solubility. For IR products manufactured
with these substances, a similar assumption should be
2.3. BA /BE waiver for class I drugs? acceptable as with Class I dosage forms: If their dissolu-
tion is rapid under all physiologic pH conditions, it can be
Principally, both guidelines consider a waiver of BA or expected that they will also behave like an oral solution in
BE studies for rapidly dissolving drug products containing vivo.
compounds of high solubility and high permeability (Class Consequently, it seems appropriate to consider a waiver
I). The motivation for such a regulation is the assumption of BA / BE studies also for this type of IR products.
that such products may behave in vivo like an oral solution Moreover, there are additional arguments which may
for which bioavailability is considered self-evident. As a underscore Class III drugs as even better candidates in this
consequence, since dissolution of Class I drugs is expected respect. For these compounds, permeation through the
to be very fast, BA / BE studies seem unnecessary for such intestinal membrane will be the rate limiting process for
products. drug absorption. Under such circumstances, rate and extent
This general concept sounds conclusive. If the Class I of bioavailability is not so much dependent on the release

Fig. 3. In vitro dissolution (left graph, mean curves, n56) and mean plasma profiles (right graph, n512) of two indometacine C / MR generics of the
German market (Steinigen, 1984; Blume et al., 1988).
120 H.H. Blume, B.S. Schug / European Journal of Pharmaceutical Sciences 9 (1999) 117 – 121

Fig. 4. In vitro dissolution (left graph, mean curves n56) and mean plasma profiles (right graph, n514) of four IR ranitidine dosage forms (Polli, 1997).

properties of the formulation but on the in vivo permeabili- bioavailability will be affected only by the in vivo per-
ty pattern. This deduction is supported by the following formance of the dosage form if dissolution is rate-limiting
example (Fig. 4). for drug absorption. In contrast, as long as the permeation
For this study, several batches of an IR ranitidine through the intestinal membrane is the slowest (and thus
product were manufactured exhibiting different bio- rate-limiting) process, bioavailability and consequently
pharmaceutical properties. However, although the dosage also bioequivalence are not so much dependent on the
forms showed obvious deviations in dissolution, superim- release properties of the dosage form.
posable plasma concentration vs. time profiles were ob- As a consequence, solid oral medicinal products with
served in vivo. This behaviour may be explained by the very rapid dissolution in all physiological media (entire pH
BCS. As ranitidine is a Class III drug with high solubility range) may be considered as minor problematic regarding
and low permeability, the rate and extent of its bioavail- bioavailability. For such preparations, it is reasonable to
ability is ‘‘controlled’’ primarily by the permeation process expect that they would behave in vivo like oral solutions
and not so much by in vivo drug release. and thus, that their bioavailability would be dependent
Thus, in case of Class III compounds, bioavailability more on gastric emptying than on the drug product
will be very much independent of the drug dissolution properties. However, this general consideration does not
properties of the galenical form. Consequently, generic necessarily imply that such (generic) products are per se
products of Class III drugs with differing in vitro dissolu- bioequivalent to a given reference product (as this may
tion will not necessarily exhibit also different in vivo exhibit different dissolution properties). Nevertheless, bio-
performance. However, it has to be taken into considera- equivalence can be assessed in such cases by comparing in
tion that low permeability compounds are often character- vitro dissolution profiles of test and reference under all
ised by site dependent absorption properties. Consequently physiological pH conditions and prove their sufficient
their bioavailabilities (rate and extent) will also depend on similarity.
the transport velocity through the GI tract and thus, may be This concept is relevant not only for Class I drugs as
strongly affected by excipients which modify the GI transit mentioned by the current Guidelines, but principally also
time (e.g. mannitol (Adkin et al., 1995)). for Class III compounds. Moreover, the latter seem to be
even better candidates for a waiver of BA / BE studies as
their bioavailabilities are primarily dependent on per-
3. Conclusions meability properties of the drug substance. As a conse-
quence, also in cases of certain differences in dissolution
BA / BE studies are requested in the regulatory process between generic products of Class III compounds, their
with different intentions: bioavailabilities should be similar due to the fact that drug
absorption is not so much affected by the (in vivo) release
• to investigate the impact of the dosage form properties from the dosage form but ‘‘controlled’’ by the (permeabili-
on drug absorption (rate and extent) or ty) properties of the active drug ingredient.
• to draw conclusions on clinical efficacy and safety from On the other hand special attention should be paid to
the measured plasma concentrations (correlation with excipients which are known to modify GI transit (e.g.
pharmacodynamic and toxicological effects). certain sugar alcohols) or drug absorption (e.g. enhancers).
As some Class III drugs exhibit site dependent (low)
The BCS was primarily developed for a better under- permeabilities their absorption may be affected by such
standing of the relationship of drug release (in vivo) from excipients. Consequently, for the decision process regard-
the product and the absorption process. In this respect, the ing bio-waivers a further specification of the BCS (as
question of the rate-limiting step is of primary relevance. described in Fig. 1) is suggested by inclusion of dissolu-
According to current thinking in science and technology, tion properties and introduction of sub-classes for the Class
 H.H. Blume, B.S. Schug / European Journal of Pharmaceutical Sciences 9 (1999) 117 – 121 121

Fig. 5. Biopharmaceutical classification of drug substances and product characteristics as basis for a potential waiver of in vivo BA / BE studies.

III compounds depending on certain excipients used in ¨

Blume, H., Ali, S.L., Stenzhorn, G., Stuber, W., Siewert, M., 1985. Zur
¨
Bioverfugbarkeit und pharmakodynamischen Aktivitat ¨ handelsublicher
¨
their formulations (Fig. 5).
¨ ¨
Glibenclamid-Fertigarzneimittel, 3. Mitt.: Bioaquivalenzprufung an
In conclusion, by extending the existing proposals gesunden Probanden unter Dauerinfusion von Glucoselosung. ¨ Pharm.
mentioned in the current guidelines, a waiver of BA / BE Ztg. 130, 2605–2610.
studies should also be granted for rapidly dissolving oral ¨
Blume, H., Stuber, ¨
W., Stenzhorn, G., Sorgel, F., 1988. Untersuchungen
IR products containing Class III drug substances with the ¨
zur Bioverfugbarkeit von Indometacin-Retardzubereitungen, 1. Mitt.:
Ergebnisse einer Single-dose-Studie. Pharm. Ztg. Wiss. 1 / 133, 12–20.
supposition that the products do not contain excipients
CPMP Note for Guidance on the Investigation of Bioavailability and
which may modify GI transit or the absorption process. Bioequivalence (CPMP/ EWP/ QWP/ 1401 / 98 Draft), December 1998.
FDA Guidance for Industry Dissolution Testing of Immediate Release
Solid Oral Dosage Forms, August 1997.
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