The Biopharmaceutics Classification System is a system to differentiate the drugs on the basis of their solubility and permeability.^[1]

This system restricts the prediction using the parameters solubility and intestinal permeability. The solubility classification is based on a United States Pharmacopoeia (USP) aperture. The intestinal permeability classification is based on a comparison to the intravenous injection. All those factors are highly important because 85% of the most sold drugs in the United States and Europe are orally administered^{[citation needed]}.

BCS classes[edit]

According to the Biopharmaceutical Classification System (BCS) drug substances are classified to four classes upon their solubility and permeability:^[1]

• Class I - high permeability, high solubility
  • Example: metoprolol, paracetamol^[2]
  • Those compounds are well absorbed and their absorption rate is usually higher than excretion.
• Class II - high permeability, low solubility
  • Example: glibenclamide, bicalutamide, ezetimibe, aceclofenac
  • The bioavailability of those products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found.
• Class III - low permeability, high solubility
  • Example: cimetidine
  • The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied.
• Class IV - low permeability, low solubility
  • Example: Bifonazole
  • Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.

Definitions[edit]

The drugs are classified in BCS on the basis of solubility, permeability, and dissolution.

Solubility class boundaries are based on the highest dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 to 7.5. The volume estimate of 250 ml is derived from typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water.

Permeability class boundaries are based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane. Alternatively non-human systems capable of predicting drug absorption in humans can be used (such as in-vitro culture methods). A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 90% or more of the administered dose based on a mass-balance determination or in comparison to an intravenous dose.

For dissolution class boundaries, an immediate release product is considered rapidly dissolving when no less than 85% of the labeled amount of the drug substance dissolves within 15 minutes using USP Dissolution Apparatus 1 at 100 RPM or Apparatus 2 at 50 RPM in a volume of 900 ml or less in the following media: 0.1 N HCl or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.

See also[edit]

• ADME

References[edit]

1. ^ ^abMehta M (2016). Biopharmaceutics Classification System (BCS): Development, Implementation, and Growth. Wiley. ISBN978-1-118-47661-1.
2. ^https://www.ema.europa.eu/documents/scientific-guideline/draft-paracetamol-oral-use-immediate-release-formulations-product-specific-bioequivalence-guidance_en.pdf

Further reading[edit]

• Folkers G, van de Waterbeemd H, Lennernäs H, Artursson P, Mannhold R, Kubinyi H (2003). Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability (Methods and Principles in Medicinal Chemistry). Weinheim: Wiley-VCH. ISBN3-527-30438-X.
• Amidon GL, Lennernäs H, Shah VP, Crison JR (March 1995). 'A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability'. Pharm. Res. 12 (3): 413–20. PMID7617530.

External links[edit]

• BCS guidance of the U.S. Food and Drug Administration

Abstract

The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Essential Medicines to determine the distribution of BCS Class 1, 2, 3, and 4 drugs in Abbreviated New drug Applications (ANDA) submissions. To categorize solubility and intestinal permeability properties of generic drugs under development, we used a list of 61 drugs which were classified as BCS 1, 2, 3, and 4 drugs with certainty in the World Health Organization Model List of Essential Medicines. Applying this list to evaluation of 263 ANDA approvals of BCS drugs during the period of 2000 to 2011 indicated 110 approvals (41.8%) for Class 1 drugs (based on both biowaiver and in vivo bioequivalence studies), 55 (20.9%) approvals for Class 2 drugs, 98 (37.3%) approvals for Class 3 drugs, and no (0%) approvals for Class 4 drugs. The present data indicated a trend of more ANDA approvals of BCS Class 1 drugs than Class 3 or Class 2 drugs. Antiallergic drugs in Class 1, drugs for pain relief in Class 2 and antidiabetic drugs in Class 3 have received the largest number of approvals during this period.

INTRODUCTION

The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability which are the major characteristics of a drug substance that control its absorption in vivo (). According to the BCS classification approach, drug substances have been grouped into one of the four categories as Class 1 (high solubility, high permeability), Class 2 (low solubility, high permeability), Class 3 (high solubility, low permeability), and Class 4 (low solubility and low permeability). The US Food and Drug Administration (US FDA) implemented guidance based on BCS to waive in vivo bioavailability and bioequivalence study requirements to approve drug products (2). Biowaivers can be granted if the active pharmaceutical ingredient (API) is BCS Class 1, i.e., a drug substance of high solubility and high permeability, and if the immediate-release (IR) oral formulation exhibits rapid in vitro dissolution (2). The BCS-based biowaiver approval has also been adopted by the European Medicines Agency and World Health Organization (WHO) for IR oral drug products (). The WHO guidance recommends biowaivers for APIs that belong to BCS Class 1 and Class 3 and also certain APIs from BCS Class 2 (4). It is important to emphasize that the US FDA considers granting biowaivers only for Class 1 drugs but does not use the WHO BCS Class 1 list to grant such biowaivers. Rather, the US FDA follows the criteria described in its Guidance for Industry on the BCS (2) and considers the applicant's submitted solubility/permeability data on API and dissolution data on the drug product in deciding whether a Class 1 biowaiver is appropriate.

An in vivo bioequivalence (BE) study is the accepted test to ensure therapeutic equivalence of a generic product to its corresponding reference product. The BCS-based BE study waiver is becoming an important tool in approving generic drug products by US FDA. Initially, BCS-based BE study waivers were granted only for Scale-Up and Post Approval Changes (5). Later, this was implemented to approve generic IR oral drug products of BCS Class 1 API. BCS biowaivers are not granted to drug products with a narrow therapeutic range and drug products designed to be absorbed in the oral cavity. In vivo bioequivalence study waivers help to avoid unnecessary human exposure to drugs. In addition, biowaivers reduce the cost and time of developing generic IR oral drug products and also decrease regulatory burden ().

In the present study, to gain an understanding of the solubility and intestinal permeability properties of generic drugs under development in the USA, we examined the distribution of BCS Class 1, 2, 3, and 4 drugs in ANDA submissions based on the WHO Model List of Essential Medicines (EML) having sufficient solubility and permeability data for BCS classification with certainty (). The WHO Model List of Essential Medicines was used merely to describe generic drug solubility and intestinal permeability properties because it is publicly available and includes BCS Class 1, 2, 3, and 4 designations. However, as stated previously, to determine whether a generic drug is eligible for a BCS biowaiver, the FDA follows its own criteria set forth in its BCS Guidance for Industry (2).

METHODS

An internal FDA database was applied to identify generic drugs approved during the 2000 to 2011 period. For determining the distribution of BCS Class 1, 2, 3, and 4 drugs in ANDA submissions, we used the approved generic drug products of immediate-release oral dosage forms listed on the WHO EML having sufficient solubility and permeability data for BCS classification with certainty.

RESULTS AND DISCUSSION

We evaluated 263 approved generic drugs of IR products listed on the WHO EML to find out the distribution of BCS Class 1, 2, 3, and 4 drugs in approved ANDA applications during the 2000 to 2011 period. The WHO EML was used as it is a publicly available list of Class 1, 2, 3, and 4 drugs. Some of the FDA-approved oral IR ANDA products which are not listed in the WHO EML could not be considered for the study mainly due to insufficient solubility and permeability data for BCS classification with certainty. Of the 130 orally administered drugs on the WHO EML, 61 drugs have been classified as BCS 1 (21 drugs), 2 (10 drugs), 3 (24 drugs), and 4 (6 drugs) drugs with certainty (). ANDA approval data from 2000 to 2011 were analyzed to determine how many BCS Class 1, 2, 3, and 4 drugs from the list of 61 drugs were developed and approved as generic drugs based on both BCS biowaivers (applicable only for Class 1) and BE studies. The results indicated 110 (41.8%) approvals for Class 1 drug products, 55 (20.9%) approvals for Class 2 drug products, and 98 (37.3%) approvals for Class 3 drug products (Fig. 1). Figure 2 shows the yearly approval of different BCS Class generic drug products during this period. There were no approvals for WHO EML BCS Class 4 drug products during the 2000 to 2011 period. Thirty two different therapeutic classes of IR products of BCS Class 1, 2, and 3 were approved during this period. Of these 32 different therapeutics classes, antiallergic drugs in Class 1, drugs for pain relief in Class 2, and antidiabetic drugs in Class 3 have received the largest number of approvals.

The percent approval of different classes of BCS drugs listed on WHO EML from 2000 to 2011

ANDA approvals of WHO EML BCS Class drug products from 2000 to 2011 based on BCS biowaivers and in vivo BE studies

As stated above, the US FDA grants biowaivers based on the applicant's submitted solubility/permeability data on API and dissolution data on the drug product. We evaluated the quality of BCS biowaiver ANDA applications submitted to the FDA and noted some commonly occurring deficiencies. These deficiencies are mostly associated with solubility and permeability studies on API and are listed below:

• Lack of multi-pH solubility profiles

• Inappropriate method of solubility determination

• Lack of dissolution data for all strengths

• Missing standard operating procedures for analytical methods

• Missing data supporting gastrointestinal stability

• Lack of data on efflux transporter(s) in the cell line used for in vitro permeability

• Lack of bidirectional in vitro permeability data on control model compounds

The above information is provided to assist applicants who submit BCS biowaiver requests to the FDA to prepare high-quality submissions. We hope that publication of this information on commonly occurring deficiencies associated with BCS biowaiver ANDA applications will promote application and review efficiency.

CONCLUSION

The data presented in this study on 32 different therapeutic classes of BCS generic drugs approved by the US FDA during the 2000–2011 period indicated the following ANDA approval trend: BCS Class 1 > Class 3 > Class 2, with no BCS Class 4 drugs evaluated. Antiallergic drugs in Class 1, drugs for pain relief in Class 2, and antidiabetic drugs in Class 3 have received the largest number of approvals.

References