Translating Cellular Science into Human Outcomes

Biopharmaceutics Classification System

Now the industry standard, more than 90% of non-clinical data submitted and accepted for BCS biowaivers is derived from Caco-2 testing. Our extensively validated test system accurately predicts the fraction absorbed in humans. The FDA explicitly recommends the BCS approach for many drugs and welcomes data for any qualified candidate. Furthermore, for Class I compounds, it is unlikely that absorption will be limited by efflux transporters. Thus, it may be possible to waive clinical DDI studies as well. Here’s an example of how and which clinical studies you could potentially waive by using Absorption Systems’ dually validated Caco-2 test system:

P-gp Interaction Study BCRP Interaction Study
Substrate Assessment
    • Caco-2 vs. CPT-P1
Inhibition Assessment
    • Caco-2
    • Clinically Relevant Probe Substrate
BCS Classification Study
    • Caco-2 Cells
Possibly Waive:
    • Clinical P-gp Study
    • Human BA/BE

 

Substrate Assessment
    • Caco-2 vs. CPT-B1
Inhibition Assessment
    • CPT-P1
    • Clinically Relevant Probe Substrate
BCS Classification Study
    • Caco-2 Cells
Possibly Waive:
    • Clinical BCRP Study
    • Human BA/BE

 


Biopharmaceutics Classification System
Avoid expensive and time consuming clinical bioequivalence studies with in vitro solubility, permeability, and dissolution data. It is a critical optimizer in time and money for drug developers.

BCS Classification

BCS Biowaivers Background Information
Biopharmaceutics Classification System (BCS) is a regulatory mechanism through which drug developers and generic companies can obtain a waiver of clinical bioequivalence studies, also called a biowaiver.

BCS Classification Studies Per Year

A Decade of BCS History
Absorption Systems has performed dozens of BCS studies over the past ten years, resulting in some of the very first BCS biowaivers granted by the FDA.


Redefining the Threshold for Permeability Classification
The permeability threshold defined by Absorption Systems novel High Permeability Internal Standard is the lowest available, about 7-fold less than metaprolol.

BCS Classification

Welcome to the BCS Zone
Watch this video and learn more about BCS biowaivers from our President and CEO, Patrick Dentinger.


Biopharmaceutics Classification System IND Tabbed Module

Recent enhancements to our study design enable favorable classification of a broader range of compounds, including cytotoxic and highly variable drugs. Such improvements include use of a novel high permeability standard, test system validation at multiple pH levels, and alternative designs for low-recovery compounds. We take a 3-step approach to BCS classification.

Phase 1A: BCS Pre-Qualifying Screen
Bidirectional permeability of test compound is evaluated at a single concentration across Caco-2 cell monolayers. Test compound is co-dosed with minoxidil (high permeability) and atenolol (low permeability) reference standards. This pre-qualifying screen allows for comparison of test compound permeability vs. control compounds and determination of passive transport (bidirectional symmetry). It also confirms the suitability of test conditions for classification of the compounds.

Phase 1B: Non-GLP Protocol Optimization
This protocol optimization step prior to GLP study includes non-specific binding assessment, tolerability evaluation, bidirectional permeability assessment in the absence of control compounds and optional solubility evaluation.

Phase 2: Pivotal GLP BCS Study
The definitive classification study includes GLP validation of analytical method and permeability assessment at three concentrations of test compound.

EA901 Preliminary BCS Solubility
EA902 GLP BCS Solubility
EA903 Preliminary BCS Permeability
EA904 GLP BCS Permeability

>> View all assays

EA202 Express Bidirectional Caco-2
EA814 Rat Closed Loop Intestinal Perf
EA815 Rat Single Pass Intestinal Perf
EA816 Rat Recirculating Intestinal Perf
EA232 BCRP Interaction Assessment Lev 2
EA233 BCRP Interaction Assessment Lev 3
EA234 BCRP Interaction Assessment Lev 1
EA240 P-gp Interaction Assessment
EA250 Express P-gp Substrate in CPT-B1
EA251 Express BCRP Substrate in CPT-B1
EA252 Express P-gp Substrate in CPT-P1
EA820 Express Rodent Brain to Plasma Ratio

>> View all assays

Abrahamsson B. et al., The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension. J Pharm Pharmacol. 2005 Mar; 57(3):273-85.

Amidon, GL, et al., Gastric pH influences the appearance of double peaks in the plasma concentration-time profiles of cimetidine after oral administration in dogs. Pharm. Res. 1995; 12:780-786.

Artursson P, et al., Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev. 2001 Mar 1; 46(1-3):27-43.

Barends DM, et al., Biowaiver monographs for immediate release solid oral dosage forms: Ranitidine hydrochloride. J Pharm Sci. 2005 Aug; 94(8):1617-25.

Fabre G, et al., Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line: comparison with the parental Caco-2 cell line. Pharm Res. 1998 May; 15(5):726-33.

Gotoh Y, et al., The advantages of the Ussing chamber in drug absorption studies. J Biomol Screen. 2005 Aug; 10(5):517-23.

Hidalgo IJ, et al., Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterol. 1989; 96:736-49.

Sambuy Y, et al., The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics. Cell Biol Toxicol. 2005 Jan;21(1):1-26.

Varma MV, et al., Biopharmaceutic classification system: a scientific framework for pharmacokinetic optimization in drug research. Curr Drug Metab. 2004 Oct; 5(5):375-88. Review.

Zhang, L, et al., Scientific Perspectives on Drug Transporters and Their Role in Drug Interactions. Mol Pharm, 2006 Jan; 3 (1): 62-9.

In Vitro Permeability and Solubility Study of Mefloquine Hydrochloride According to the Biopharmaceutics Classification System (BCS) Guidelines (Poster, BA/BE World Congress Las Vegas 2011)

Comparison of Non-Clinical Intestinal Permeability Techniques (In Vitro, In Situ, and Ex Vivo) for BCS Classification (Poster, BA/BE World Congress Las Vegas 2011)

>> Resource Library

Which compounds are eligible for BCS-based biowaivers?
BCS biowaivers may apply for both generics and NCE’s. According to the FDA Guidance (2000), immediate release solid oral dosage forms that exhibit high solubility (over the pH range 1-7.5), high permeability (as qualified in a validated test system with internal standard) and high dissolution, are eligible for BCS-based biowaivers of clinical BA/BE studies. The EMA permits biowaivers for both Class I (high solubility/high permeability) and Class III (high solubility/low permeability) compounds. Some argue that biowaivers should be permitted for some Class II compounds as well.

Which methods are acceptable for permeability classification?
The FDA Guidance (2000) permits the use of human PK studies (absolute bioavailability or mass balance studies) and intestinal permeability methods (in vivo human intestinal perfusion, in vivo or in situ animal intestinal perfusion, excised human or animal intestinal tissue, or in vitro cultured epithelial cell monolayers) as methods to determine permeability classification.

Which studies can be bypassed with a BCS-based biowaiver?
After initial bioavailability studies, additional bioavailability or bioequivalence studies may be waived. Requests for biowaivers can be made in one of three types of regulatory submissions to the FDA:
• Investigational New Drug (IND) applications, for drugs under development
• New Drug Applications (NDAs) to market new drug products
• Abbreviated New Drug Applications (ANDAs) to market generic drug products

The following studies may be waived: clinical drug-drug interaction studies, bioequivalence studies for line extensions based on dose proportionality, formulation changes, approval of generic drug products, post-approval changes in manufacturing formula, manufacturing process, excipients, manufacturing site/equipment.

Absorption Systems is the world leader in biopharmaceutics classification system. We have been performing BCS studies for over a decade, and we supported the very first in vitro BCS-based biowavier.

For us, BCS is routine. Our experienced staff perform, on average, more than 30 studies per year and have uniquely classified more than 100 compounds.

We are innovators in the field and utilize an internal HPIS, minoxidil, which has a Papp value of approximately 7-fold less than metoprolol, leading to more accurate compound classifications.

Our proven track record with the FDA, including successful site audits and training sessions, can't be matched by any of our competition.

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