Biopharmaceutics Classification System (BCS) and Biowaivers: Role in Drug Product Design

_{Anshu Sharma*}¹_{, CP Jain}¹ _{, MS Ashawat}²

¹Department of Pharmaceutical Sciences, M.L.S. University Udaipur(Rajasthan)

²B.N. Girls College of Pharmacy, Udaipur, (Rajasthan)

 

ABSTRACT

 

The introduction of the Biopharmaceutics Classification System (BCS) into the Food and Drug Administration is a major step  forward  to  classify  the  biopharmaceutical properties  of  drugs  and  drug  products.  Based  on  the  mechanistic approaches to the drug absorption and dissolution process, the BCS enables the regulatory bodies to simplify and improve the drug approval process. The knowledge of BCS of drug in a formulation can also be utilized by the formulation scientist to develop a more optimized dosage form.

 

 

_{INTRODUCTION:}

The Biopharmaceutics Classification System¹ (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 necessary steps for a drug to be absorbed are (a) release of drug from dosage forms,

(b) Maintenance of dissolved state throughout gastrointestinal (GI) track, and (c) Permeation of drug molecules through GI membrane into hepatic circulation. (d) Enterohepatic metabolism that influences the systemic availability as well as release of metabolites into the systemic circulation.

 

Y. Wu and L. Z. Benet²  proposed Biopharmaceutical Drug Disposition Classification System (BDDCS) completes the absorption process by including the fourth rate-limiting step of first pass effect. 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 optimization³. It is arguable 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. Biopharmaceutic Classification System, provides drug designer an opportunity to manipulate structure or physicochemical properties of lead candidates so as to achieve better "deliverability". Considering the facts for failure of New Chemical Entity (NCEs), drug research, once concentrating on optimizing the efficacy and safety of the leads, dramatically transformed in the past two decades

 

 

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

 

Purpose of the BCS Guidance:

 

•      Expands  the  regulatory  application  of  the  BCS  and recommends methods for classifying drugs.

 

If the regulatory utility of dissolution tests for IR products are to be expanded, their   reliability must be improved⁴. For

 

IR products this may be achieved by considering the mechanistic relationships between drug dissolution, physico-chemical characteristics of drugs, gastrointestinal physiology and absorption or permeation processes.  To  this  effect  BCS  provides, with minimal reliance on in vivo pharmacokinetic data, a rational mechanistic frame work for developing reliable dissolution tests for assessing bioequivalence.

 

•      Explains when a waiver for in vivo bioavailability and  bioequivalence  studies  may  be   requested based on the approach of BCS.

 

The BCS also provides a means for identifying when dissolution in vivo is likely or not likely to be rate- limiting and allows for managing risks associated with reliance on in vitro dissolution for bioequivalence assessment.

 

Biopharmaceutics Classification System (BCS)

This system, pioneered by Professor Amidon, all drug

molecules are classified into one of four classes based on their solubility and permeability through the intestinal cell layer. The classes are as follows:

 

Class1 : The drugs belongs to this class exhibit a high dissolution and absorption. The rate limiting step is drug dissolution and if dissolution is very rapid then gastric  emptying  rate  becomes the  from  rate determining step⁵. Class I consists of water-soluble drugs that are well absorbed the gastrointestinal tract and,  in  general,  have  the  preferred physicochemical properties. For immediate release dosage forms the absorption rate will be controlled by the gastric emptying rate. However, to secure constant high bioavailability, the dissolution rate must be relatively fast, or over 85% dissolution in 15 minutes.

 

Class 2: These drugs have a high absorption rate and a low dissolution therefore absorption is  limited primarily by  drug  dissolution in  the  gastrointestinal tract. In vivo drug dissolution is then a rate limiting step for absorption except at a very high dose. Class II consists of water-insoluble drugs which, when dissolved, are well absorbed from the gastrointestinal tract. The dissolution rate in vivo is usually the rate- limiting step in drug absorption. Commonly drugs in this class have variable absorption due to the numerous formulation effects and in vivo variables that can affect the dissolution profile. Various formulation techniques are applied to compensate for the insolubility of the drugs and the consequent slow dissolution rate. These include formulation of the amorphous solid form, nanoparticles, surfactant addition, salt formation and

complexation.⁶ By such techniques the formulator tries to move the drugs from Class II to Class I without changing the intrinsic ability of the drug molecules to permeate biomembranes.

Class 3: These drugs have high dissolution and low absorption. In vivo permeability is rate limiting step for drug absorption. These drugs exhibit a high variation in the rate and extent of drug absorption. Since the dissolution is rapid, the variation is attributable to alteration of physiology and membrane permeability rather than the dosage form factors. Class III consists of water-soluble drugs that do not readily permeate biomembranes. For these drugs the Rate limiting factor in drug absorption is their permeability⁷. Including absorption enhancing excipients in their formulation can enhance their bioavailability.

 

Class 4: It consists of water-insoluble drugs which when solubilized do not readily penetrate biomembranes. These drugs are usually very difficult to formulate for effective oral delivery.

 

The interest in this classification system stems largely from its application in early drug development⁸ and then in the management of  product  change  through  its  life-cycle.  In early  drug  development  knowledge  of  the  class  of  a particular  drug  is  an  important  factor  influencing  the decision to continue or stop its development. Obviously a low solubility/low permeability drug will never be presented as   an   orally   administered   product   and   will   probably encounter serious formulation difficulties. A company wishing to produce an oral dosage form will wish to limit its development to those molecules that have high permeability. Increasingly, these considerations are incorporated from the very earliest phases, with the concept of property-based design being used in combinatorial chemistry to target production of compounds showing optimal properties. Subsequent in vitro models are then applied to evaluate the drug in early development.

 

 

In    Vitro    Dissolution    Tests    and    Bioequivalence

Assessment: Need for BCS

The large regulatory interest in the BCS comes from its combination with in vitro – in vivo correlation (IVIVC)⁹  to manage the  issues of  product quality throughout its  life- cycle. For example, orally administered class II drugs are expected to show a correlation between observed dissolution rate in vitro and rate and extent of absorption in vivo. The correlation is expected as it is the rate of release from the product  that  is  the  controlling  factor  in  the  absorptive process, the intestinal barrier not being rate-limiting. A reliable  IVIVC  can  therefore  be  used  to  predict  in vivo performance based on in vitro results. This tool would thus permit an assessment of the effect of change on in vivo product performance based on in vitro tests. This change is incurred  for  all  products  at  several  stages,  for  example: scale-up change of manufacturing site, excipients, suppliers etc. At its most extreme, this could be a change of manufacturer, i.e. a generic product, and raises the ultimate possibility of approval of certain generic drugs using comparative in vitro results only. For class I drugs, which dissolve rapidly and are highly permeable, bioavailability problems, are  not  to  be  expected and  dissolution testing could suffice to assure bioequivalence in the circumstances discussed above.

 

On rare occasions an inverse in vitro - in vivo relationship, i.e., higher peak drug concentration in blood for a product that exhibits a relatively slow rate of dissolution in vitro, in a particular media, compared with another product, have also been observed. Such examples of "failure" of in vitro dissolution tests¹⁰  to signal bio-in-equivalence have hindered the use of dissolution tests for assessing bioequivalence between two pharmaceutically equivalent products. Comprehensive research studies designed to elucidate mechanistic reasons for such failures are generally not available in the public domain. Also, data from such failed  studies  are  generally  not  submitted  to  the Agency. Possible causes for such differences may include; 1) inappropriate specification (dissolution test conditions, primarily media composition, and acceptance criteria), (2) presence of an excipient that may alter drug absorption, and (3) other reasons (for example, statistical type II error).

 

Experience gained through development of traditional in vitro - in vivo correlations (e.g., Level A, B, or C correlations) for immediate release (IR) products containing  poorly  soluble  drugs  and  for  extended release products suggests a significant degree of formulation dependency or specificity associated with such  correlations.  Therefore,  for  products  that  are likely to exhibit slow in vivo dissolution, in vitro - in vivo correlations need to be established and their predictive performance verified through experimentation. Future research in  this  area  should address how to a priori identify dissolution test conditions   that   yield   robust   in   vitro   -   in   vivo correlations that are applicable to a wide range of formulations.

 

BIO-WAIVERS BASED ON THE BCS

The   BCS   are   adopted   by   the   World   Health Organization (WHO), and classifies the drug molecules listed on the essential medicines list (EML)¹¹ based on their  solubility  and  permeability  characteristics  into four different classes. The use of in vitro testing to achieve  a  waiver  of  in  vivo  studies  is  commonly referred to as a biowaiver.  Certain drug classes to be considered for a biowaiver, i.e. approval of products based on their in vitro drug dissolution tests instead of their human bioequivalence data, which is a costly task for drug manufacturers. By utilizing in vitro parameter such biowaivers significantly improve the speed and decrease the cost of bringing orally administered formulation to market. Currently, the BCS system allows a waiver of in vivo bioequivalence testing of immediate-release solid dosage forms for class 1 drugs. Whereas waivers for class 3 drugs are recommended only based on scientific justifications. Recent research has lead to the use of in-vitro tests to waive additional in vivo bioequivalency studies for some pharmaceutical products. The opportunities for cost-reduction through the limitation of costly in vivo studies make this a current and widely-debated topic. The BCS Working Group of the FDA proposed subsequent draft guidance that a ‘bio-waiver’ (i.e. assessment of bioequivalence using in  vitro testing only) could be considered for class I drugs, provided they meet a list of criteria. Considering the uncertainties associated with in vitro dissolution tests, the proposed draft guidance recommends biowaivers only for rapidly dissolving products of highly soluble and highly permeable drugs that are not considered, by the FDA, to be "Narrow Therapeutic Index Drugs." The criterion for defining the therapeutic index of a drug is currently under consideration at the FDA. It is proposed that BCS based biowaivers apply for situations during both pre- (IND/NDA and ANDA) and post approval phases.  The  FDA  guidance  outlines  five  categories  of biowaivers⁸.

1.    Biowaivers without an IVIVC,

2.    Biowaivers  using  an  IVIVC:  non-narrow  therapeutic index drugs,

3.    Biowaivers using an IVIVC: narrow therapeutic index drugs,

4.    Biowaivers when in vitro dissolution is independent of dissolution test conditions and situations for which an IVIVC is not recommended for biowaivers

 

Biowaiver      Consideration     Active      Pharmaceutical Ingredient (API)

In  order to  be  considered bioequivalent according to  the FDA Biowaiver procedure, a pharmaceutical product:

• Should contain a class 1 substance

• Should be rapidly dissolving, meaning it should release at least 85% of its content in 30 minutes in three different buffers (pH 1.2, pH 4.5 and pH 6.8) 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 influence the absorption of the drug

• Should not contain a drug with a narrow therapeutic index

•  Should  not  be  designed  to  be  absorbed  from  the  oral cavity.

 

The reasoning for the above-mentioned class 1 substance, dissolution restriction is that when a highly soluble, highly permeable drug dissolves rapidly, it behaves like a solution in the gastrointestinal tract. If excipients give insignificant data, it should be excluded from the formulation because it influence the uptake across the gut wall and ultimately influence the bioavailability. The API is not prone to precipitation after its dissolution due to its good solubility under all  pH  conditions likely to  be  found in  the  upper gastrointestinal tract. The high drug permeability assures the complete  uptake  (>  90%)  of  the  API  during its  passage through the small intestine. The fast dissolution of the product guarantees that the API is available long enough for the uptake in small intestine (the passage time in the small intestine is approximately 4 hours) and negates any slight differences between the formulations. Pharmaceutical products containing an API with a narrow therapeutic index should always be tested with in vivo methods, since the risk for the patient resulting from a possible incorrect bioequivalence decision using the Biowaiver procedure is considered too high with these kinds of APIs. As the BCS is only applicable to drugs which are absorbed from the small intestine, drugs with different sites of absorption   (oral   cavity)   are   not   eligible   for   a Biowaiver. It can be easily seen that the FDA requirements for classification of APIs and eligibility criteria for the Biowaiver are very strict. In the last decade, several scientific data and continuing discussions have suggested that the original FDA criteria for application of the Biowaiver procedure can be relaxed without substantially increasing the risk to public health or to the individual patient. On the basis of these data and dialogue, the WHO has proposed revised BCS criteria and additional considerations for the eligibility of a pharmaceutical product for the Biowaiver procedure in the Multisource document¹².

 

Protocol for Biowaivers

Required Data for 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 (pH 1.2,4.5, 6.8).¹³

• Data  supporting  similarity  in  dissolution  profiles between the test and reference products in each of the three media, using the f2 metric.

 

Required Data for High Permeable drugs:

• 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.

Required Data for Highly Soluble drugs:

•      Information on chemical structure, molecular weight, nature of drug substance, dissociation constants.

•      Description of test methods (analytical method, buffer composition).

•      Test results summarized in a table with solution pH, drug solubility, and  volume  to  dissolve highest dose strength.

•    Graphical representation of mean pH-solubility profile

 

Methodology for the Dissolution Characteristics of a

Drug Product

The following approaches are recommended for classifying  a    drug    substance    and    determining    the    dissolution characteristics of an IR drug product according to the BCS.

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.

 

A. 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.

 

An objective of the BCS approach is to determine the equilibrium  solubility  of  a  drug  substance  under physiological pH conditions. The pH-solubility profile of the test drug substance should be determined at 37 ± 1oC in aqueous media with a pH in the range of 1-7.5.¹⁴ A sufficient number of pH conditions should be evaluated to accurately define   the   pH-solubility   profile.   The   number   of   pH conditions for a solubility determination can be based on the ionization characteristics of the test drug substance. Depending on study variability, additional replication may be  necessary to  provide a  reliable  estimate of  solubility. Standard   buffer   solutions   described   in   the   USP   are considered appropriate for use in solubility studies. Methods other than the traditional shake-flask method, such as acid or base titration methods, can also be used with justification to support the ability of such methods to predict equilibrium solubility of the test drug substance. Concentration of the drug substance in selected buffers (or pH conditions) should be determined using a  validated stability-indicating assay that can distinguish the drug substance from its degradation products.  The  solubility  class  should  be  determined  by calculating the volume of an aqueous medium sufficient to