Pharmaceutical Research, Vol. 19, No. 7, July 2002 (© 2002)
`
`Commentary
`
`Biopharmaceutics Classification System: The Scientific Basis
`for Biowaiver Extensions1
`
`Lawrence X. Yu,2,6 Gordon L. Amidon,3 James E. Polli,4 Hong Zhao,2 Mehul U. Mehta,2
`Dale P. Conner,2 Vinod P. Shah,2 Lawrence J. Lesko,2 Mei-Ling Chen,2 Vincent H. L. Lee,5
`and Ajaz S. Hussain2
`
`KEY WORDS: Biopharmaceutics Classification System; solubility; permeability; dissolution; bio-
`equivalence; immediate-release products.
`
`INTRODUCTION
`
`Since the introduction of the Biopharmaceutics Classifi-
`cation System (BCS) (1), its validity and applicability have
`been the subject of extensive research and discussion (2).
`These efforts have resulted in an improved SUPAC-IR guid-
`ance (3), a dissolution guidance (4), and a Food and Drug
`Administration (FDA) guidance on waiver of in vivo bio-
`equivalence studies for BCS Class I drugs in rapid dissolution
`immediate-release (IR) solid oral-dosage forms (5). The BCS
`guidance generally is considered to be conservative with re-
`spect to the class boundaries of solubility and permeability in
`addition to the dissolution criteria. Thus, the possibility modi-
`fying these boundaries and criteria to allow waivers of in vivo
`bioequivalence studies “biowaivers” for additional drug prod-
`ucts has received increasing attention (6). In this commentary,
`we present a discussion of the relevant scientific issues that
`have been or will be examined when extensions of biowaivers
`to additional IR solid oral drug products are considered. It is
`hoped that this commentary will stimulate more discussion in
`the scientific community and ultimately result in new regula-
`tory policies.
`
`BIOPHARMACEUTICS CLASSIFICATION
`SYSTEM (BCS)
`
`The BCS is a scientific framework for classifying a drug
`substance based on its aqueous solubility and intestinal per-
`
`1 Opinions expressed in this report are those of the authors who are
`affiliated with the Food and Drug Administration and do not nec-
`essarily reflect the views or policies of the Food and Drug Admin-
`istration.
`2 Food and Drug Administration, Center for Drug Evaluation and
`Research, Office of Pharmaceutical Science, 5600 Fishers Lane,
`Rockville, Maryland 20857.
`3 Department of Pharmaceutics, University of Michigan, College of
`Pharmacy, Ann Arbor, Michigan 48109-1065.
`4 Department of Pharmaceutical Sciences, University of Maryland,
`School of Pharmacy, Baltimore, Maryland 21201.
`5 Department of Pharmaceutical Sciences, University of Southern
`California, School of Pharmacy, Los Angeles, California 90089-
`9121.
`6 To whom correspondence should be addressed. (e-mail: yul@cder.
`fda.gov)
`
`meability (1). When combined with the in vitro dissolution
`characteristics of the drug product, the BCS takes into ac-
`count three major factors: solubility, intestinal permeability,
`and dissolution rate, all of which govern the rate and extent of
`oral drug absorption from IR solid oral-dosage forms (5).
`The solubility classification of a drug in the BCS is based
`on the highest dose strength in an IR product. A drug sub-
`stance is considered highly soluble when the highest strength
`is soluble in 250 mL or less of aqueous media over the pH
`range of 1.0–7.5; otherwise, the drug substance is considered
`poorly soluble. The volume estimate of 250 mL is derived
`from typical bioequivalence study protocols that prescribe the
`administration of a drug product to fasting human volunteers
`with a glass (about 8 ounces) of water.
`The permeability classification is based directly on the
`extent of intestinal absorption of a drug substance in humans
`or indirectly on the measurements of the rate of mass transfer
`across the human intestinal membrane. Animal or in vitro
`models capable of predicting the extent of intestinal absorp-
`tion in humans may be used as alternatives, e.g., in situ rat
`perfusion models and in vitro epithelial cell culture models. A
`drug substance is considered highly permeable when the ex-
`tent of intestinal absorption is determined to be 90% or
`higher. Otherwise, the drug substance is considered to be
`poorly permeable.
`An IR drug product is characterized as a rapid-
`dissolution product when not less than 85% of the labeled
`amount of the drug substance dissolves within 30 min using
`USP Apparatus I at 100 rpm or USP Apparatus II at 50 rpm
`in a volume of 900 mL or less of each of the following media:
`1) acidic media, such as 0.1 N HCl or USP simulated gastric
`fluid without enzymes; 2) a pH 4.5 buffer; and 3) a pH 6.8
`buffer or USP simulated intestinal fluid without enzymes.
`Otherwise, the drug product is considered to be a slow dis-
`solution product.
`
`FDA GUIDANCE ON BIOWAIVERS
`
`The FDA issued a guidance for industry on waivers of in
`vivo bioavailability and bioequivalence studies for IR solid
`oral-dosage forms based on the BCS in August 2000 (5). This
`BCS guidance recommends that sponsors may request bio-
`waivers for highly soluble and highly permeable drug sub-
`
`921
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`0724-8741/02/0700-0921/0 © 2002 Plenum Publishing Corporation
`
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`Yu et al.
`
`stances (Class I) in IR solid oral-dosage forms that exhibit
`rapid in vitro dissolution, provided the following conditions
`are met: 1) the drug must be stable in the gastrointestinal
`tract; 2) excipients used in the IR solid oral-dosage forms
`have no significant effect on the rate and extent of oral drug
`absorption; 3) the drug must not have a narrow therapeutic
`index; and 4) the product is designed not to be absorbed in the
`oral cavity.
`Based on the scientific principles of the BCS, observed in
`vivo differences in the rate and extent of absorption of a drug
`from two pharmaceutically equivalent solid oral products may
`be due to in vivo differences in drug dissolution. When the in
`vivo dissolution of an IR oral dosage form is rapid in relation
`to gastric emptying, the rate and extent of drug absorption is
`likely to be independent of drug dissolution. Therefore, simi-
`lar to oral solutions, demonstration of in vivo bioequivalence
`may not be necessary as long as the inactive ingredients used
`in the dosage form do not significantly affect the absorption
`of the active ingredient. Thus, for BCS Class I (high solubil-
`ity-high permeability) drug substances, demonstration of
`rapid in vitro dissolution using the recommended test meth-
`ods would provide sufficient assurance of rapid in vivo disso-
`lution, thereby ensuring human in vivo bioequivalence. In our
`opinion, the potential benefit of this FDA guidance is not
`only lowering expenditures associated with bioavailability/
`bioequivalence studies but more critically expediting the de-
`velopment of new chemical entities for the marketplace, en-
`tities that will ultimately be of benefit to the health of the
`American public.
`
`BIOWAIVER EXTENSION POTENTIAL
`
`Potential of Redefining BCS Solubility Class Boundary
`
`The solubility class boundary requires that the highest
`strength of a drug substance is soluble in 250 mL or less of
`aqueous media over the pH range of 1.0–7.5. The pH range of
`1.0–7.5 for solubility studies is a stringent requirement and
`may not be necessary. Under fasting conditions, the pH range
`in the GI tract vary from 1.4 to 2.1 in the stomach, 4.9 to 6.4
`in the duodenum, 4.4 to 6.6 in the jejunum, and 6.5 to 7.4 in
`the ileum (9). Furthermore, it generally takes approximately
`85 min for a drug to reach the ileum (8). By the time the drug
`reaches the ileum, the dissolution of the drug product is likely
`complete if it meets the rapid dissolution criterion, i.e., no less
`than 85% dissolved within 30 min. Therefore, it would appear
`reasonable to redefine the pH range for BCS solubility class
`boundary from 1.0–7.5 to 1.0–6.8 in alignment with dissolu-
`tion pH ranges, which are pH 1.0, 4.5, and 6.8 buffers.
`The dose volume of 250 mL seems a conservative esti-
`mate of what actually is available in vivo for solubilization
`and dissolution. The physiological volume of the small intes-
`tine varies from 50 to 1100 mL with an average of 500 mL
`under the fasted conditions (10). When administered with a
`glass of water, the drug is immersed in approximately 250 mL
`of liquid in the stomach. If the drug is not in solution in the
`stomach, gastric emptying would then expose it to the small
`intestine, and the solid drug would dissolve under the effect of
`additional small intestinal fluid. However, because of the
`large variability of the small intestinal volume, an appropriate
`definition of the volume for solubility class boundary would
`be difficult to set.
`
`Another factor influencing in vivo solubility is bile salt/
`micelle solubilization (11). Intestinal solubility is perhaps the
`most important solubility because this is the absorbing region
`for most drugs. Many acidic drugs whose solubility is low at
`low pH are well absorbed. For example, most nonsteroidal
`anti-inflammatory drugs, such as flurbiprofen, ketoprofen,
`naproxen, and oxaprozin, are poorly soluble in the stomach
`but are highly soluble in the distal intestine and their absolute
`human bioavailabilities are 90% or higher, thus exhibiting
`behavior similar to those of BCS Class I drugs (7).
`The solubility classification is based on the ability of a
`drug to dissolve in plain aqueous buffers. However, bile salts
`are present in the small intestine, even in the fasted state. The
`average bile salt concentration in the small intestine is esti-
`mated to be approximately 5 mM (9). Based on physiological
`factors, Dressman designed two kinds of media, one to simu-
`late the fasted-state conditions in the small intestine and the
`other to simulate the fed-state conditions in the small intes-
`tine (9). These two media may be used in drug discovery and
`development processes to assess in vivo solubility and disso-
`lution and have the potential to be used in drug regulation,
`i.e., dissolution methodology for bioequivalence demonstra-
`tion using more physiologically relevant media, although
`more extensive research is needed.
`Other criteria, such as intrinsic dissolution rate, may be
`useful in the classification of the biopharmaceutic properties
`of drugs. The intrinsic dissolution method has been widely
`used in pharmaceutical industries to characterize drug sub-
`stances. Our recent data have shown that the intrinsic disso-
`lution method is robust and easily determined. A good cor-
`relation between the intrinsic dissolution rate and BCS solu-
`bility classification was found for 17 BCS model drugs (12).
`Thus, the intrinsic dissolution rate may be used when the
`solubility of a drug cannot be accurately determined, al-
`though more validation research needs to be conducted.
`
`Potential of Redefining BCS Permeability Class Boundary
`
`The permeability class boundary is based on the extent of
`intestinal absorption (fraction of dose absorbed) of a drug
`substance in humans or on measurements of the rate of mass
`transfer across intestinal membranes. Under the current BCS
`classification, a drug is considered to be highly permeable
`when the fraction of dose absorbed is equal to or greater than
`90%. The criterion of 90% for the fraction of dose absorbed
`can be considered conservative because the experimentally
`determined fraction of dose absorbed is seen to be less than
`90% for many drugs that are generally considered completely
`or well-absorbed. This suggests that a class boundary of 85%
`might be appropriate in defining high permeability, although
`it remains to be justified and debated.
`
`Biowaiver Extension Potential to BCS Class II Drugs
`
`BCS Class II drugs exhibit low solubility and high per-
`meability characteristics. The scientific rationale for granting
`biowaiver extension for Class II drugs is that their oral ab-
`sorption is most likely limited by in vivo dissolution. If in vivo
`dissolution can be estimated in vitro, it is possible to establish
`an in vitro-in vivo correlation. In vitro dissolution methods
`that mimic in vivo dissolution methods for Class II drugs are
`appealing, but experimental methods can be difficult to de-
`
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`

`Biopharmaceutics Classification System
`
`923
`
`sign and to validate because of the numerous in vivo pro-
`cesses involved (9). Further, the intestinal absorption of Class
`II drugs can be limited by its solubility (13). The key deter-
`minant then is the solubility in the absorbing region of the
`intestine. The solubilization can be affected by pH and/or
`surfactants in this region. This suggests a potential to define
`an intermediate solubility class for drugs that are soluble ei-
`ther in the intestine or in the stomach.
`The dissolution of formulations containing poorly
`soluble drugs may require an addition of sodium lauryl sulfate
`or other surfactants to mimic the solubilization in vivo and the
`maintenance of sink conditions in vivo resulting from con-
`tinuous absorption. For example, the recommended USP
`dissolution media for medroxyprogesterone acetate tablet,
`danazol capsule, carbamazepine tablet, and flutamide tablet
`contain 0.5%, 0.75%, 1%, and 2% SLS, respectively (USP
`24-NF19, 2001). Although the dissolution medium with vari-
`ous surfactant concentrations may be adequate for the pur-
`pose of product quality control, this is clearly not sufficient for
`predicting in vivo dissolution. There is a need to do more
`research to develop uniform dissolution media reflecting in
`vivo dissolution conditions.
`For BCS Class II drugs, excipients can, in principle, affect
`both solubility and permeability. Some BCS Class II drugs,
`such as HIV protease inhibitor amprenavir, require specific
`formulation effort to enhance their solubility and permeabil-
`ity (14). An excipient effect on solubility can be investigated
`in vitro and ex vivo, and more research of this type is under-
`way.
`
`Biowaiver Extension Potential to BCS Class III Drugs
`
`Drugs with high solubility and low permeability are clas-
`sified as BCS Class III drugs. It has been suggested that bio-
`waivers be extended to BCS Class III drugs with rapid disso-
`lution property. It has been contended that there are equally
`compelling reasons to grant biowaivers to Class III drugs as
`there are for Class I drugs (6).
`
`Scientific Rationale
`
`The absorption of a Class III drug is likely limited by its
`permeability and less dependent upon its formulation, and its
`bioavailability may be determined by its in vivo permeability
`pattern (6,15). If the dissolution of Class III products is rapid
`under all physiological pH conditions, it can be expected that
`they will behave like an oral solution in vivo. In vivo bio-
`equivalence studies generally are waived for oral solution
`drug products because the release of the drug from an oral
`solution is self-evident (16).
`Nevertheless, the absorption kinetics from the small in-
`testine are influenced by a combination of physiological fac-
`tors and biopharmaceutical properties such as gastrointestinal
`motility, permeability, metabolism, dissolution, and the inter-
`action/binding of drugs with excipients (18,19). A recent sur-
`vey of the FDA data of over 10 BCS Class III drugs shows
`that most commonly used excipients in solid dosage forms
`have no significant effect on absorption. If the excipients used
`in two pharmaceutically equivalent solid oral IR products do
`not affect drug absorption and the two products dissolve very
`rapidly in all physiologically relevant pH ranges (i.e., > 85%
`
`in 15 min), there would appear to be no reason to believe that
`these two products would not be bioequivalent.
`
`Potential Excipient Effect on Motility and Permeability
`
`Because Class III compounds often exhibit site-depen-
`dent absorption properties (17,18), the transit time through
`specific regions of the upper intestine may be critical for bio-
`equivalence, suggesting a more stringent dissolution criterion
`to ensure complete dissolution in the stomach. Certain excipi-
`ents have been shown to influence gastrointestinal transit
`time. For example, scintigraphy has indicated that sodium
`acid pyrophosphate could reduce the small intestinal transit
`time by as much as 43% compared to controls (19). Poorly
`absorbed sugar alcohols, such as sorbitol and mannitol, can
`also decrease small intestinal transit time (20). Therefore,
`Class III oral drug products containing a significant amount of
`transit-influencing excipients should be excluded from con-
`sideration of biowaivers. Although most commonly used ex-
`cipients in solid dosage forms are unlikely to influence the
`gastrointestinal transit time significantly, the evidence by no
`means is conclusive.
`The effects of excipients on permeability have been re-
`viewed in the literature (21). Excipients that can significantly
`affect permeability in vitro include surfactants, fatty acids,
`medium-chain glycerides, steroidal detergents, acyl carni-
`tine and alkanoylcholines, N-acetylated non-␣ amino acids,
`chitosans, and other mucoadhesive polymers. Rege et al.
`(22) investigated the effect of some formulation excipients
`on Caco-2 permeability and found that several commonly
`used IR formulation excipients did not modulate drug per-
`meability across Caco-2 monolayers.
`
`Dissolution
`
`In vivo dissolution plays a more important role for Class
`III IR drug products than it does for Class I drug products.
`Dissolution tests with USP Apparatus I at 100 rpm (or USP
`Apparatus II at 50 rpm) in a volume of 900 mL of various pH
`media are recommended in the FDA guidance to evaluate the
`product dissolution in vitro. For highly soluble and highly
`permeable drugs, rapid dissolution in vitro (no less than 85%
`in 30 min) can most likely ensure rapid in vivo dissolution.
`However, the demonstration of rapid in vitro dissolution of
`Class III drug products may not ensure rapid dissolution in
`vivo simply because sink conditions may not exist under in
`vivo conditions. To minimize the possibility of dissolution
`behavior anomalies, it was found in our simulation studies
`that it would be necessary to set a more rapid in vitro disso-
`lution rate criterion of no less than 85% within 15 min for
`Class III drugs (23).
`
`Transporters
`
`Numerous in vitro Caco-2 studies have suggested that
`transporters may enhance or limit the absorption of many
`drugs such as digoxin and HIV protease inhibitors, including
`indinavir, ritonavir, and saquinavir (15,24). On the other
`hand, many transporter substrates show complete intestinal
`absorption and dose proportionality in vivo, implying that
`transporters do not significantly influence in vivo absorption.
`This apparent discrepancy between in vitro and in vivo
`behavior may be explained by the potential inherent differ-
`
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`
`Yu et al.
`
`ences in the two systems as well as by the experimental con-
`ditions adopted in the comparisons. For example, a new
`chemical entity was found to be a strong P-glycoprotein sub-
`strate and was classified as a low permeability compound
`based on in vitro Caco-2 studies. However, its absolute bio-
`availability in humans was greater than 90%, and dose pro-
`portionality was demonstrated over a 60-fold dose range. The
`concentration of the compound in the in vitro Caco-2 studies
`was approximately 3400-fold lower than the estimated con-
`centration in vivo, which may account for the large discrep-
`ancy between the in vivo and the in vitro findings of its per-
`meability characteristics. Thus, in vitro studies must be ex-
`trapolated to in vivo with great care. Nevertheless, the
`potential impact of transporters on absorption should be thor-
`oughly investigated and understood when considering bio-
`waiver extensions.
`
`Intermediate Permeability Classification
`
`In general, the lower the permeability of a Class III drug,
`the more significant the effect of excipients on absorption and
`the higher the likelihood of bioinequivalence. Therefore, it
`has been proposed to define an intermediate permeability
`class so that drugs with 89% fraction of dose absorbed would
`not be treated the same as drugs with 1% fraction of dose
`absorbed. However, how to define the intermediate perme-
`ability class remains to be addressed.
`
`SUMMARY
`
`The current BSC guidance issued by the FDA allows for
`biowaivers based on conservative criteria. Possible new crite-
`ria and class boundaries are proposed for additional biowaiv-
`ers based on the underlying physiology of the gastrointestinal
`tract. The proposed changes in new class boundaries for solu-
`bility and permeability are as follows:
`
`1. Narrow the required solubility pH range from 1.0–7.5
`to 1.0–6.8.
`2. Reduce the high permeability requirement from 90%
`to 85%.
`
`The following new criterion and potential biowaiver exten-
`sion require more research:
`
`1. Define a new intermediate permeability class bound-
`
`ary.
`
`2. Allow biowaivers for highly soluble and intermedi-
`ately permeable drugs in IR solid oral dosage forms with no
`less than 85% dissolved in 15 min in all physiologically rel-
`evant dissolution media, provided these IR products contain
`only known excipients that do not affect the oral drug ab-
`sorption.
`
`The following areas require more extensive research:
`
`1. Increase the dose volume for solubility classification
`to 500 mL.
`2. Include bile salt in the solubility measurement.
`3. Use the intrinsic dissolution method for solubility
`classification.
`4. Define an intermediate solubility class for BCS Class
`II drugs.
`5. Include surfactants in in vitro dissolution testing.
`
`ACKNOWLEDGMENT
`
`We would like to thank Donna Volpe and Christopher
`Ellison for their valuable suggestions.
`
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`