Automation of Dissolution Tests
for Biowaiver Studies
Rolf Rolli
SOTAX Group, Allschwil, Switzerland

email for correspondence: rolf.rolli@sotax.ch

Recent research has lead to the use of in-vitro tests to waive additional in vivo bioequivalency studies for some pharmaceutical products. The use of in vitro testing to achieve a waiver of in vivo studies is commonly referred to as a biowaiver.This article describes the use of automated dissolution instrumentation and software for biowaiver studies.

Speed of drug introduction to the marketplace is a key success factor for a pharmaceutical company. Fast development and launch of a drug result in significant economic gains for a drug manufacturer. A recent FDA guidance based on a Biopharmaceutics Classification System (BCS) permits waiver of in vivo Bioavailability and Bioequivalencey studies. The Biopharmaceutics

Classification System classifies drugs as follows:

Class 1: High Solubility - High Permeability
Class 2: Low Solubility - High Permeability
Class 3: High Solubility - Low Permeability
Class 4: Low Solubility - Low Permeability

In vitro tests for solubility, permeability and dissolution form the basis of a drug product's classification and qualification for biowaivers.

Current regulations permit waivers for Class 1 rapidly dissolving drugs, which represent up to 25% of the drugs. Efforts in science and regulatory bodies are being made to extend biowaivers to certain Class 2 and 3 products, which would represent more than 50% of all drugs coming on the market.

In vivo bioavailability and bioequivalencey studies cost up to $ 250,000 each and can require up to 2 months to complete. On the other hand, in vitro laboratory tests are rather inexpensive and fast. Dissolution studies, f 2 profile calculations and report writing represent a large part of the laboratory work. SOTAX offers an automated dissolution system with software designed for biowaiver testing. The fully automated Dissolution test system AT 70smart can perform multiple runs with different media/pH. (Figure 1)

Figure 1: SOTAX AT 70smart

With this system up to 10 USP 2 tests can be fully automated, from the tablet input up to the print out of the report.

The AT 70smart is designed to:
· Dispense 3 different media and water
· deliver the medium to all vessels simultaneously
· drain and clean all vessels simultaneously
· deaerate medium with helium sparging
· remove sample aliquots using the hollow shaft sampling system
· allow the use of different filter membranes
· analyze samples using on-line UV or off-line HPLC
· perform up to10 tests.

Test with baskets require the Basket-Station BS 60. (Figure 2) Up to 10 USP 1 tests can be loaded.

Figure 2: SOTAX AT 70smart with Basket station BS 60

The system is thoroughly cleaned after each test using water. Prior to initiating the next test the vessels are pre-rinsed with the selected test medium. The programmed cleaning procedure:
· drains the medium from the vessels through valves at the bottom of the vessels
· rinses the vessels multiple times with rotating spray heads at 4 bar pressure allowing the removal of any sticky residue
· cleans all tubing and filter stations using high pressure reversed sparging
· removes any remaining liquid in lines with a final air purge.

This cleaning procedure significantly reduces the risk of carry over and cross contamination.
The AT70smart system utilizes CFR 21 Part 11 compliant software, WinSOTAX. WinSOTAX software for biowaiver testing contains standard check boxes for test type, medium type and volume selection, speed and sampling time. Check boxes are activated and used for each parameter setting. The regulations require the testing of 12 test samples and 12 references samples for dissolution profile comparison. Similarity factor, f2 calculations, are performed on the stored results and a report is generated with comparison profiles, f2 calculations, statistics and a pass/fail comment for the dissolution profile similiarity (f2) criteria.

The WinSOTAX software offers the following user input options:

Method Generator Check boxes:

__USP Apparatus I at 100 rpm (Default)
__USP Apparatus II at 50 rpm (Default)
__Immediate Release Product
__Extended Release Product

Selectable media:

__0.1 N HCl, 900 ml (Default)
__pH 4.5 buffer, 900 ml (Default)
__pH 6.8 buffer, 900 ml (Default)
Any other media may be added

Pre-programmed sampling points:
__Immediate Release products 10, 15, 20, 30 and 60 minutes
__Extended Release products 1, 2, 3, 5 and 8 hours

Biowaiver Report Generator
Sample Description:
· Description
· Strength
· Batch or lot number
Check Boxes for BCS Class:
__Class 1: High Solubility - High Permeability
__Class 2: Low Solubility - High Permeability
__Class 3: High Solubility - Low Permeability
__Class 4: Low Solubility - Low Permeability
The final report will contain:
· Mean percent dissolved
· Range (highest and lowest) of dissolution
· Coefficient of variation (relative standard deviation)
· Graph of the mean dissolution profiles for the test and reference products in all media
· f2, similarity factor, calculation; if f2 value is above 50 the qualification statement "Passed Requirement for Biowaiver" appears.
Graph 1: Example of Dissolution Profile
Recent FDA guidances permit the waiver of additional in vivo studies for pharmaceutical products that meet specified criteria. Costly and time consuming in vivo studies may be replaced by fast and low cost in vitro tests. The AT 70smart dissolution system can be an efficient tool for biowaiver studies due to automation of the testing process and biowaiver calculations.