Biopharmaceutical Classification System and Formulation Development

Introduction:

The Biopharmaceutics Classification System (BCS) is not only a useful tool for obtaining waivers for in vivo bioequivalence studies but also for decision making in the discovery and early development of new drugs. It is because BCS is based on a scientific framework describing the three rate limiting steps in oral absorption. The three necessary steps for a drug to be absorbed are release of drug from dosage forms, maintenance of dissolved state throughout gastrointestinal (GI) track, and permeation of drug molecules through GI membrane into hepatic circulation. There is a fourth step, i.e. enterohepatic metabolism that influences the systemic availability as well as release of metabolites into the systemic circulation. The Biopharmaceutical Drug Disposition Classification System (BDDCS) proposed by Y. Wu and L. Z. Benet completes the absorption process by including the fourth rate-limiting step of first pass effect.

The evaluation of these four steps of oral absorption is critical to the discovery of orally efficacious drugs. Consequently the determination of solubility, permeability, and metabolic stability have been fully integrated by most pharmaceutical companies as an integral part of high throughput screening (HTS) and lead optimization. These oral absorption screening tests are often referred as pharmaceutical profiling and automated 96 well systems are available from commercial sources. It is argue-able that application of BCS in lead compound selection for optimal chemistry may be more important than using BCS in biostudy waiver at a later development stage. After all, the aim of pharmaceutical industry is to discover better compounds not in doing less biostudies.

The pharmaceutical scientist in early development routinely utilizes pharmaceutical profiling data to establish the preliminary BCS classification for the lead compound. Because BCS has ramification in drug approval process from FDA and other regulatory agencies, it carries some weight when used as a tool of communication. During the discovery of new drugs, classification of a compound to BCS 2, BCS 3 or BCS 4 communicates to Discovery the need to improve solubility and/or permeability for subsequent compounds. In the same vein, a BCS classification other than 1 communicates to Manufacturing that may lead to higher formulation risks during drug development. Most importantly, it warns the clinician of the potential for a large variability in exposure and a significant food effect.

With the advent of high throughput screening around 1990, a shift of lead compound biopharmaceutical characteristics into less drug-like has propelled discovery departments in pharmaceutical companies to utilize computational chemistry to optimize solubility and permeability such as Lipinski’s “rule of 5”. This shift is recently reflected in the different distributions among the four BCS classes between the marketed and the new pipeline compounds. The new drug pipeline tends to have lower solubility resulting in an increase of BCS 2 compounds from ~30% to 50–60% and the corresponding decrease of BCS 1 compounds from ~40% to 10–20%. It is critical for the industry to continuously integrate the BCS principles into new drug discovery. Moreover, BCS classification may be utilized as the basis for polymorph/salt and formulation selections in early drug development as discussed in this paper.

The BCS based drug discovery strategy imparts quality by designing the lead compound with a set of solubility, permeability and metabolic properties. The BCS based polymorph/salt form and formulation strategies can often lead into a minimum design for higher efficiency and lower cost. It is in line with FDA’s year 2000 risk management and 2004 critical path initiatives to streamline new drug development.

Purpose of the BCS Guidance: 

• Expands the regulatory application of the BCS and recommends methods for classifying drugs.
• Explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the approach of BCS.

Goals of the BCS Guidance:

• To improve the efficiency of drug development and the review process by recommending a strategy for identifying expendable clinical bioequivalence tests.
• To recommend a class of immediate-release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests.
• To recommend methods for classification according to dosage form dissolution, along with the solubility and permeability characteristics of the drug substance.

According to the BCS, drug substances are classified as follows:

Class I - High Permeability, High Solubility
Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility

CLASS BOUNDARIES

• A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.
• A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose.
• A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions.

SOLUBILITY DETERMINATION

• pH-solubility profile of test drug in aqueous media with a pH range of 1 to 7.5.
• Shake-flask or titration method.
• Analysis by a validated stability-indicating assay.

PERMEABILITY DETERMINATION

Extent of absorption in humans:

• Mass-balance pharmacokinetic studies.
• Absolute bioavailability studies.

Intestinal permeability methods:

• In vivo intestinal perfusions studies in humans.
• In vivo or in situ intestinal perfusion studies in animals.
• In vitro permeation experiments with excised human or animal intestinal tissue.
• In vitro permeation experiments across epithelial cell monolayers.

DISSOLUTION DETERMINATION

• USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm.
• Dissolution media (900 ml): 0.1 N HCl or simulated gastric fluid, pH 4.5 buffer, and pH 6.8 buffer or simulated intestinal fluid.
• Compare dissolution profiles of test and reference products using a similarity factor (f₂).

BCS BIOWAIVER

• Rapid and similar dissolution.
• High solubility.
• High permeability.
• Wide therapeutic window.
• Excipients used in dosage form used previously in FDA approved IR solid dosage forms.

REQUEST FOR BIOWAIVERS

Data Supporting Rapid and Similar Dissolution

• A brief description of the IR products used for dissolution testing.
• Dissolution data obtained with 12 individual units of the test and reference products at each specified testing interval for each individual dosage unit. A graphic representation of the mean dissolution profiles for the test and reference products in the three media.
• Data supporting similarity in dissolution profiles between the test and reference products in each of the three media, using the f₂ metric.

Data supporting High Permeability:

• For human pharmacokinetic studies, information on study design and methods used along with the pharmacokinetic data.
• For direct permeability methods, information supporting method suitability with a description of the study method, criteria for selection of human subjects, animals, or epithelial cell line, drug concentrations, description of the analytical method, method to calculate extent of absorption or permeability, and information on efflux potential (if appropriate).
• A list of selected model drugs along with data on the extent of absorption in humans used to establish method suitability, permeability values and class for each model drug, and a plot of the extent of absorption as a function of permeability with identification of the low/high permeability class boundary and selected internal standard.
• Permeability data on the test drug substance, the internal standards, stability information, data supporting passive transport mechanism where appropriate, and methods used to establish high permeability of the test drug substance.

Data supporting High Solubility:

• Description of test methods (analytical method, buffer composition).
• Information on chemical structure, molecular weight, nature of drug substance, dissociation constants.
• Test results summarized in a table with solution pH, drug solubility, volume to dissolve highest dose strength.
• Graphical representation of mean pH-solubility profile.

For further information visit the BCS guidance "Waiver of In-vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System."[PDF].

BCS Class in Pharmaceutical Industry:

The Biopharmaceutical Clas­sification System (BCS) is an ex­perimental model that measures permeability and solubility under prescribed conditions. The origi­nal purpose of the system was to aid in the regulation of post-approval changes and generics, providing approvals based solely on in vitro data when appropriate. Importantly, the system was de­signed around oral drug delivery since the majority of drugs are and remain orally dosed. Waivers, permission to skip in vivo bio­equivalence studies, are reserved for drug products that meet cer­tain requirements around solubil­ity and permeability and that are also rapidly dissolving.

More and more however, the industry is using the BCS as a tool in drug product develop­ment. As a simple example, BCS can be used to flag drugs that should not be tested clini­cally unless appropriate formu­lation strategies are employed. As an example, a BCS Class II compound, per­meable but relatively insoluble, would likely not be a good clini­cal candidate without the use of enhanced formulation tech­niques aimed at increasing solu­bility or rate of dissolution. Vari­ous schemes exist that attempt to funnel a given API towards par­ticular drug delivery techniques depending on the API’s BCS category. Still, most approaches remain fragmented in their meth­odology, ignoring commercially and biologically important fac­tors. The BCS can however, when integrated with other information provide a tremendous tool for ef­ficient drug development. One school of thought, very much endorsed by the authors, is that first in human (FIH) drug dos­age forms should be designed to maximize bioavailability and that the FIH dosage form should be a logical step towards commercial­ization and not simply a stop gap  to facilitate data acquisition. This makes sense both economically and ethically.

For BCS Class I molecules, FIH formulations are straight forward and may consist of essentially the neat API. For other compounds, effective dosage forms present greater challenges. Although de­signed originally to classify APIs as to their oral bioavailability, properly augmented, the BCS can be used as a key component of an algorithm to guide drug de­livery system design for any route of administration. This notion has been elaborated on by a number of authors.

Briefly, the BCS places a giv­en API in one of four categories depending on its solubility and permeability as they pertain to oral dosing. A drug substance is considered “highly soluble” when the highest clini­cal dose strength is soluble in 250 mL or less of aqueous media over a pH range of 1–7.5 at 37 °C. A drug substance is consid­ered to be “highly permeable” when the extent of the absorp­tion (parent drug plus metabo­lites) in humans is determined to be ≥90% of an administered dose based on a mass balance  determination or in comparison to an intravenous reference dose2. Permeability can be determined a number of ways but is most of­ten done using Caco-2 cell lines an assay that lends itself to high throughput automation. In this system, a monolayer of cells is grown and drug permeation from the drug donor (apical side) to the acceptor (basolateral side) com­partments is assessed, usually by using a direct UV or LC-MS assay. Potential issues with Caco-2 based systems range from variation (from in vivo) in transport mechanisms to drug interactions with the ap­paratus itself. Commercial com­panies focused on this assay have developed multiple approaches to alleviate these issues but a review is beyond the scope of this paper and the reader is encouraged to contact the various suppliers. As a drug candidate moves up the de­velopment ladder, developers will often confirm and refine their BCS assessments with increasingly complex in vivo models.

An important subtlety here is that the BCS accounts for potency in that solubility and permeabil­ity are relative to clinical dose. Again, oral dosing is assumed in the testing design. So, for ex­ample, a compound that has poor absolute solubility might para­doxically be classified as “highly soluble” if it were a highly potent compound and the whole clinical dose was soluble in 250 mL.

 BCS and Dosage Form Trends:

It is commonly recognized that most new drugs present formu­lation challenges. In fact, older drugs as compared to newer ones have higher solubilities in general. One reference noted that BCS Class II compounds as a percent­age of compounds under develop­ment had increased from 30% to 60%. BCS Class I compounds have fallen correspondingly from 40% to 20% over that same pe­riod3. In practice, low solubility is the most common theme encoun­tered. In our own experience the majority of compounds formu­lated at Particle Sciences on the behalf of our clients have low to no aqueous solubility. It should be noted that not every drug is classified the same by each investigator. The variability can be due to a number of things including the way permeability is measured. As above, in vivo per­meability is impacted by, among other things, drug transporters. Both uptake and efflux transport­ers exist and can contribute to the differences seen by the vari­ous techniques.

For the majority of APIs a solid oral dosage form (SOD) is the preferred option. Sometimes the physicochemical and physi­ologic mechanisms do not allow this and alternatives are pursued such as suspensions or oral so­lutions. Other times, the target and other factors dictate that a non-oral dosage form is most sen­sible. Examples include the lo­cal delivery of female hormones, nasal allergy preparations, ocular therapeutics and combination products aimed at prolonged drug release. In all these cases, even though not orally dosed, the concepts inherent in the BCS can be important tools in dosage form design.

Formulation Approach:

Having a pre-defined system in which one can make decisions based on data is necessary for ef­ficient drug development. Inputs into such a system include, in addition to BCS class, a detailed solubility profile, polymorph sta­tus, desired dosage form, target dose and dosing regimen, drug stability, excipient compatibility and knowledge of transporter and metabolic pathways. Non-tech­nical factors that, as a practical matter, need to be considered are such things as cost, intellectual property and distribution chain limitations. Integration of these into a methodical systematic ap­proach will maximize the chances of a successful outcome. As R&D dollars become ever more scarce, it becomes increasingly evident that early consideration of as many factors as possible is the most ef­ficient way to proceed. This is true independent of the route of administration. In practice, this leads to the strategy of getting to FIH as quickly as possible with a formulation strategy that accounts for both physicochemical proper­ties and physiologic influences.

A complete set of algorithms covering the four classes and all possible dosage forms is well be­yond the scope of this article. However, a few fundamental prin­ciples can be covered. First, it is critical to characterize your com­pound. Understanding the basic behavior of a given compound in various solvents and across a range of pHs is fundamental to designing a dosage form. For in­stance, a compound soluble only at lower pHs will require a differ­ent formulation than one freely soluble at, for example, pH 7. Likewise, a soluble yet imperme­able compound will require yet another strategy. Very importantly, this is true whether one is admin­istering the drug, for example, IV or orally. The implications to for­mulation are different for the dif­ferent routes of administration but the fact that these properties need to be accounted for is universal. It is important that the drug devel­oper or the CRO be equipped with a range of technologies to address the various patterns that emerge. Nothing wastes more time and money than trying to fit a drug to a specific preordained delivery technology.

Armed with the proper set of tools one can rapidly narrow down the potential approaches. For the most part, all drug deliv­ery strategies are trying to con­trol drug exposure. Most often, one is trying to maximize it over time and/or concentration but frequently goals also include extended release and/or site spe­cific delivery. In addition to the delivery goals, other functions are often required such as API stabilization or taste masking as two examples. In short, no one formulation approach will ever satisfy all or even a substantial portion of drug delivery demands.

For oral drug delivery, a sim­plified summary of approaches based on properties. Each approach must then be tailored to meet the oth­er demands of that particular API and desired product profile.

If formulation conditions dic­tate that a non-oral dosage form be used, similar charts exist for virtually all routes of administra­tion. Each route of administra­tion will of course have different options but they are all ruled by the interplay of the drug’s physi­cochemical properties and the local and systemic physiology they encounter.

Independent of the final dos­age form, ideal drug develop­ment involves an iterative pro­cess of setting goals, performing formulation work and develop­mental stage appropriate test­ing. Early on, for example, after physicochemical evaluations are complete, screening BCS test­ing and early polymorph screens might be performed. After thor­ough preformulation including solubility and stability testing, early formulations might again be screened for their impact on dissolution or bioavailability. This approach is repeated such that at each inflection point data is gathered to support the devel­opment plan. In this way, FIH is achieved most efficiently and in such a way as to insure clinically relevant data is obtained.

References

1.      Chi-Yuan Wu and Leslie Z. Benet, Predicting Drug Dispo­sition via Application of BCS: Transport/Absorption/Elimination Interplay and Development of a Biopharmaceutics Drug Disposi­tion Classification System, Phar­maceutical Research, January 2005, 22(1), 11-23.

2.    http://www.fda.gov/AboutFDA/CentersOffices/cder/ucm128219.htm

3.    http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm128219.htm

4.    M. Sherry Ku, Use of the Biopharmaceutical Classification System in Early Drug Develop­ment, AAPS J., March 2008, 10(1), 208–212.