Automation of Dissolution Tests

Rolf Rolli
SOTAX AG, Bassel, Swtizerland

email:rolf.rolli@sotax.ch

For many years significant time and effort has been invested in developing the automation of dissolution tests. Large pharmaceutical corporations have invested a great deal of resources in automation concepts to the point of creating task forces and/or even departments to achieve this goal. This article describes some existing possibilities for automation of dissolution testing and offers ideas for labs not having the resources to develop specific teams or departments for automation.

The reasons for automation are a result of the increase in the number of tests performed due to the following:
· Required dissolution testing of older drugs
· Increased numbers of stability tests
· Bioequivalency studies
· Increased numbers of tests per production batch

These factors require a capacity increase. In addition, an increasing number of drugs require dissolution tests running several hours in length. Often these tests have sampling points demanding overnight or even over weekend processing, resulting in the hiring of additional lab personnel. Today, with the documentation required for quality control tests and the regular eight hours per working day, it can be said that an average of about four short time tests (30 minutes each) per employee/day are possible. This results in about 800 tests per year. However, this is only true for short time tests. As soon as you increase the test length the capacity is reduced considerably. An increase in the number of tests performed will require an additional investment in manual equipment and/or laboratory staff. Important factors to consider are the cost for hiring additional personnel, and the fact that hiring is not always approved and/or in some countries cannot be found easily. Therefore more and more laboratories are investing in automation concepts.

Automation concepts offer the advantage of reproducible results. Manual tests with different personnel often create considerable discrepancy in results, resulting in high costs as production batches cannot be released or have to be re-analyzed. When designing automation solutions several method procedures need to be considered (Table 1).

Table 1: Paddle-method, USP2:

Test step	Semi-automatic system	Fully-automatic system
Medium-preparation	manually	automatic
Medium-degassing	manually	automatic
Start of the Method	automatic	automatic
Tablet dropping	automatic	automatic
Sampling	automatic	automatic
Standard monitoring	automatic	automatic
Medium addition	possible	possible
Medium replacement (part change)	possible	possible
Medium change (full)	not possible	possible
pH-Change	limited possibility	possible
Medium-Change	not possible	possible
Calculation	automatic	automatic
Emptying of vessels	manually	automatic
Cleaning of the system	manually	automatic
Start of the next test	manually	automatic

Automation can be considered for each step in the analytical procedure. "Automation concepts" can be differentiated based on their application to a single test or series of tests. Automation of a single test might require a semi-automated system, whereas, automation for a series of tests might require a fully automated system.

The following criteria needs to be considered if a laboratory focuses on automation:
· Quantity of tests
· Type of test (USP Apparatus)
· Duration of tests
· pH-changes during test
· Medium-change during test
· Time and number of sampling points
· Standard monitoring

There are different options for automation of USP 1 and 2 methods, which differ significantly from automation of USP 5 and 6 methods. USP 4 methods differ even more in the equipment concept from the other methods.
Software

WinSOTAX is an example of automated dissolution testing software. This software meets all requirements of test procedures and offers the possibility for multi-component analysis and cell grouping. WinSOTAX is fully validated and complies fully with FDA CFR Part 11 including "electronic signature".
Automation of USP 1 and 2 tests

A fully automated test instrument is the most promising solution for a high number of short time tests per year with a high sampling volume. This solution would offer the possibility to fully automate up to 15 completely different tests in series according with completely different criteria.

A semi-automated solution is of great importance when only one single test has to be automated.

Semi-automated Systems
Some semi-automated systems are based on a modular concept allowing the customer to customize all their specific testing needs. Available options include UV on-line, HPLC on-line solutions, as well as off-line, or combinations of both. Options like solvent replacement after sampling and solvent addition for pH-change are also available.

Fully automated Systems
Fully integrated automation systems manage all operations simultaneously. With some systems, like the SOTAX AT 70smart, up to 15 USP 2 tests can be fully automated from the tablet input up to the printout of the report. This system is equipped with a very efficient cleaning device, which prevents any carry over from test to test. This all adds up to time being saved in the lab. The following operations are also possible with fully automated systems:
· Solvent-addition and/or full change with up to eight different solvents
· Standard Monitoring
· Pellet Testing
· Tests with Sinkers

Tests requiring baskets can be handled with fully automated systems like the Basket-Station BS 60. This system allows up to 10 USP 1 tests to programmed.

Automation of USP 4 Tests
SOTAX along with Ciba-Geigy and Hoechst have developed this type of dissolution test which often results in better in-vivo in-vitro correlation than USP 1 and 2 tests. This method is more laborious than the USP 1 and 2 methods. Therefore SOTAX developed the CE70 Stand-alone system which is equipped with automated steps such as test preparation, solvent change and system cleaning. This system can be upgraded to a fully automated system with a Cell Feeder and WinSOTAX software for batch processing which enables the system to manage up to five tests automatically.

Automation of TTS-Patches tests
Currently there are two methods for testing of patches:
· The USP 5 method (paddle over disc)
· The USP 6 method (TTS-cylinder)

Up to now no automation concept for USP 5 method has been developed. In Europe the USP 6 method is more commonly used. In the automation of USP 6, sampling is the key issue due to the fact that in most cases patches are extended-release, e.g. hormones. Such patches are often analyzed over 96 hours with only a few samples taken (e.g. three sampling points). Because of the test length, sampling can occur during the night or during weekend hours resulting in some organizational problems. Therefore, automation of sampling is very important, while automatically changing the TTS-cylinders has not been an issue. In any case this would be even more complex to automate than the USP 1 method (baskets) and would have to follow a similar equipment concept. The automation of the sampling can be realized with automated sampling devices like the Automatic Sampling Device (ASD), an X-Y-Z robotic system. The robotic arm equipped with a syringe takes the samples, which can be filtered and filled, directly into vials. These samples can be kept cool with a Pelletier-element while awaiting further analysis.

Outlook
For many years automation concepts for dissolution laboratories were discussed and solutions were realized. At the beginning the focus was more on the hardware side and its ability to meet all needs of the lab. Now, new regulatory requirements have been published such as GAMP guidelines and the FDA CFR part 11 for software. Today, validation of the systems has become highest priority, especially for the software. Comprehensive systems have a very high level of complexity and the validation takes considerable time. Thus automation concepts for specific tasks are realized to give a high level of operational security as well as ease of validation. These systems are operated with software, which is CFR part 11 compliant with the possibility of data transfer to LIMS-Systems. Automation concept is not just a concern for large pharmaceutical companies but for mid-sized pharmaceutical companies as well. In conclusion it is intended that this article provide useful information for the evaluation of dissolution automation.