28
August/September 2010
into a registration vial using vortex & vacuum technology.
Figure 2. Impact vs Effort of proposals on reducing turnaround time Day
Time (mins)
0 20
Fractions 20
1
Process Sample Purify Analyse Transfer Evaporate Transfer Evaporate Oven Weigh Report Sample Supplied
5
(Rotary) 45
5
(Vortex) Dry & Analyse 20
60
• Total process time of 195 minutes (3.25 hours) • Process Cycle Efficiency (PCE) : 100x VA(min)/ Total Process Time(min) 100x100/195 = 51.3% • 44.4% Improvement in Efficiency! • Reduction in individual sample turnaround time from 21 hours to 3.25 hours
Table 2. Analysis of process steps in purification process following Lean Sigma optimisation 10 55 returned
By altering the methods for solvent evaporation, the purification process has become more streamlined, positively impacting the PCE as represented in Table 2.
The outcome of these improvements dramatically reduced the turnaround time to within 4 hours per sample and by adopting a workflow system, numerous samples could be processed individually throughout the working day. An example of this process work flow is shown in Figure 3.
Figure 3. Improved process work flow
It was also possible to utilize existing instrumentation, for standard flash silica normal phase chromatography. However, it was difficult to establish an effective TLC system for all compounds as some were more suited to/easier to purify using HPLC. In addition, the ambiguity of the chromatography and lack of LCMS correlation can cause this technique to be more time consuming. Inevitably, these factors prevent the suitability and routine use of flash silica rather than preparative HPLC within a service environment. Consequently, the necessity to investigate alternative solutions that could be easily incorporated with the use of prep HPLC became apparent. This focused discussion towards different methods of completing the evaporation
process and again provided support for the use of the rotary evaporators.
The second option to improve evaporation would have involved the automated use of a vortex & vacuum instrument which, as this had already been purchased required no additional cost. Unfortunately, through equipment trials this process was found to be extremely time consuming, directly impacting the overall value that could potentially be gained. It became apparent that the most effective improvement would be to routinely evaporate each sample independently. To ensure continuity throughout the system, samples would be processed by using a rotary evaporator for the aqueous fractions, re- dissolving the compound in a small amount of organic solvent, reformatting and evaporating
By using this workflow on a daily basis, it has become possible for one purification analyst to complete the purification and processing of
up to 8 sample injections per day. A visual submission process was created to aid the execution of this daily workflow, allowing for 8 submission slots ranging from 8 am to 11.30 am. Each of these slots is staggered so that a new purification is begun every 30 minutes and all samples are submitted with an LC/MS and additional compound information. To ensure continual flow throughout the day each compound is purified using a single 5 ml injection over an independently focused 17 minute gradient. The analysis of fractions generated is achieved using LC/MS, taking 5 minutes to complete each fraction. This workflow was generated with approximate average values for each process step and is not absolute. Some samples may only yield one or two fractions as opposed to the four
To successfully align our improvement plans with the requirements of the customer, it was necessary to ensure that the service also strived to deliver free flowing solids. The use of a one hour high vacuum oven drying step as a potential solution was suggested. The inclusion of this additional step was supported through the impact on overall quality delivered to the customer. This indicated the value of customer relations and by collaborative working the service was able to implement the most effective and beneficial solutions.
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