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Considerations for Automating the Dissolution Test

Considerations for Automating the Dissolution Test G. Bryan Crist e-mail: Agilent Technologies, Cary, NC. A. primary challenge for the pharmaceutical labora- qualification, and in some cases can be such an obstacle tory is to maximize throughput with optimum that the automated system implementation is delayed compliance. A technique-dependent test like or never reaches the intended level of utilization. This Dissolution is a primary target for implementing vary- results in the versatility paradox of understanding that ing levels of automation, from semiautomated sampling what we want in a system may not be what we actu- equipment to fully robotic systems. Instrumentation ally need. The ability to have a system that completely flexibility will be required in the laboratory of the future automates sampling and the analytical finish is alluring, to minimize the potential for error caused by manual yet can unnecessarily increase complexity, cost, and in intervention and to fully utilize the Dissolution appara- the end, efficiency.

44 Dissolution Technologies | MAY 2013 Considerations for Automating the Dissolution Test G. Bryan Crist Agilent Technologies, Cary, NC A primary challenge for the pharmaceutical labora -

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Transcription of Considerations for Automating the Dissolution Test

1 Considerations for Automating the Dissolution Test G. Bryan Crist e-mail: Agilent Technologies, Cary, NC. A. primary challenge for the pharmaceutical labora- qualification, and in some cases can be such an obstacle tory is to maximize throughput with optimum that the automated system implementation is delayed compliance. A technique-dependent test like or never reaches the intended level of utilization. This Dissolution is a primary target for implementing vary- results in the versatility paradox of understanding that ing levels of automation, from semiautomated sampling what we want in a system may not be what we actu- equipment to fully robotic systems. Instrumentation ally need. The ability to have a system that completely flexibility will be required in the laboratory of the future automates sampling and the analytical finish is alluring, to minimize the potential for error caused by manual yet can unnecessarily increase complexity, cost, and in intervention and to fully utilize the Dissolution appara- the end, efficiency.

2 Tus with automated sampling and on- and offline UV or HPLC analytical systems. THE CONCEPT OF Dissolution AUTOMATION. This article offers suggestions for determining the Dissolution automation begins with an evaluation of level of automation needed to obtain peak performance typical Dissolution test requirements that involve human based on the product(s), laboratory requirements, and manipulation, processing, and decision. If a series of sim- regulatory compliance associated with laboratory auto- ilar steps are routinely performed, and if the system will mation. conduct the same type of analysis, automated methods of analysis may be more desirable than manual methods THE VERSATILITY PARADOX for greater efficiency and precision. The Dissolution test Ever see an automated system sitting in the corner of is simply broken down to sample preparation using the the laboratory not being used or labeled out of service?

3 Apparatus followed by UV or HPLC analysis. These two One has to question why this happens. events are separated by filtration, which stops the dis- The primary goal of automation is to have a system solution process and clarifies the sample for analytical that will meet the needs of the laboratory. To accom- measurement. plish this goal, we must evaluate laboratory workload Dissolution consists of a series of unit operations that and the type of Dissolution samples to determine the are quite technique-dependant and may cause inconsis- most efficient configuration of automation enhance- tencies in test results when performed manually. While ment. For instance, if the typical products tested are the Dissolution test may be subdivided into many individ- 80% immediate release, 75% are Apparatus 2 paddle ual steps, five major components will be discussed regard- methods, and 70% of the products require UV analysis, ing automation: setup, Dissolution , sampling, analysis and then we should focus automation on meeting these data reduction, and finally, cleanup and changeover.

4 Since needs, possibly with an online UV Dissolution system. the entire Dissolution test is a series of these five compo- If the laboratory also requires sample archiving for in- nents, any one may be performed manually or automati- vestigation purposes, an online autosampler should be cally. If only one of the components is automated, that added to the system. step is considered semiautomated. If all five of the com- Upon consideration of implementing automated dis- ponents are automated sequentially, this approaches total solution equipment and methodology, one must review automation. Before evaluating advantages and limitations the product matrix for the particular analytical support of Automating the Dissolution test, we must first evaluate required. When automated equipment is purchased the five components of the test. without carefully targeting the specific product type or laboratory usage needs, the equipment may be insuf- Setup ficient or overly qualified for the task.

5 The equipment In Dissolution testing, there will always be some human acquired may be versatile well beyond normal testing intervention in terms of making media and setting up the requirements, may be more expensive, and may pos- apparatus. Media preparation is usually accomplished sess features that will never be used. Additional features by manual preparation, degassing, measurement, and can unnecessarily add to the burden of validation and documentation. 44 Dissolution Technologies | MAY 2013. Media dispensing may be performed gravimetrically Dissolution Sampling or volumetrically, though automated systems usually Most of the hands-on time that it takes to perform a rely on gravimetric means to deliver media. Automated Dissolution test is spent preparing for and cleaning up af- dispensing systems will generally preheat and degas ter the Dissolution test.

6 However, the most common type media but must be capable of cleaning, purging, and of semiautomation that is applied to the Dissolution test is calibrating to ensure accuracy within 1% as required in the addition of an automatic sampling system. the USP. Additionally, transfer lines must be checked to Automatic sampling may provide gains in precision ensure that they are not crimped and that the connec- over manual sampling techniques since the location, tions are tightly sealed. timing, and filtration aspects are controlled and executed The essential setup task of dosage handling to protect without variance from analysts, vessels, or both. While the sample from humidity and temperature before the time saving is vitally important, the focus on Dissolution start of the run must also be performed. Automated dos- apparatus with automated sampling indicates that one of age delivery systems must also be capable of handling the primary goals for automation is reduction of variability capsules with sinker devices attached.

7 In addition to time. Automated systems must be validated During the setup phase, automated systems should be to ensure that the proper sampling method is reproduced evaluated that components are clean will be set up with by an automated system. the proper method and filters. Other requirements include the need to rinse and purge sample lines, load and condition filters with the proper The Dissolution Apparatus amount of media, lower the sampling cannula to the The Dissolution apparatus is the sample preparation proper position, and validate that hydrodynamic factors device that determines the performance of the drug are negligible if cannulas remain in the vessel throughout release under very controlled conditions of time, tem- the test. Sampling lines must be routinely checked to perature, agitation, and volume control. Sample integrity ensure they are not damaged or crimped and are prop- must be maintained when samples are removed from erly rinsed.

8 Transfer tubing should not adsorb active drug the vessel and filtered. After filtration, the analytical product, and cleaning methods must be appropriately phase of testing occurs where the amount of active phar- validated to ensure sample integrity. maceutical ingredient (API) in solution at a specific time Automated sampling systems must be able to pull is determined quantitatively. samples precisely at the correct time interval with accu- One of the important requirements of the Dissolution rate volume, and systems that replace media must have test is maintenance of the apparatus as described in the correspondingly accurate and preheated replacement USP harmonized Dissolution chapter. Whenever a dis- volumes. Extended-release samples or those that will not solution method or procedure states that USP Apparatus be immediately analyzed must be maintained in sealed 1 basket method is used, the detailed configuration of test tubes or HPLC vials to negate concentration issues the apparatus must be followed.

9 We may use apparatus due to evaporation. modifications only if they have been properly validated for use. For example, the use of an o-ring attachment Analysis and Data Reduction and modified basket in an automated method must be Once filtered samples are obtained, the Dissolution pro- validated to show that it is equivalent to the official clip cess ends, and the samples are then evaluated typically design. Sampling probes left in the vessel during a run by UV vis spectrophotometry or HPLC. Depending on the must be verified to document that the modified ap- level of automation, the analytical finish may be on- or paratus will produce results equivalent to apparatus as offline. Justification of automated equipment should be described in USP without the probes present. based on obtaining the maximum utilization of the dis- Validation is a process that verifies the equivalence solution apparatus, sampling equipment, and the UV or of one procedure to another.

10 If there is a difference of HPLC system. greater than 2 3% between the apparatus described in Automated ultraviolet, or UV vis, systems provide an USP <711> and the modified apparatus, then the change economical and faster alternative to chromatographic is unacceptable. Likewise, temperature must be moni- methods, allowing an increased number of timepoints tored to assure proper conditions throughout the period due to the short analysis time. Advanced multicompo- of testing. nent UV vis spectroscopic systems have the potential Dropping the dosage form into non-rotating media, for being less costly than HPLC automated systems due as required in the USP, may also be challenging for some to their simplicity. These systems are ideally suited for systems. Automated systems may have multiple ports for fiber-optic analysis, but often have not gained accep- tablet introduction, sample withdrawal, and addition and tance since true separation of components does not removal of media.


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