27


introduction of an additional process step. Prior to the commencement of this project, a rapid solvent evaporator using vortex & vacuum technology was purchased for its ability to effectively evaporate reformatted individual samples using organic solvent straight into registration vials. During the initial stages of this project this system was gradually introduced, removing the second batch evaporation step in the original process, providing some initial steer for further improvements.


Figure 1. SIPOC diagram illustrating flow of compounds Day 1


Process Sample Purify Analyse Supplied


Time (mins)


0 30


Fractions Fractions 15


5 Overnight 2


Rack Evaporate Reformat Evaporate Weigh Report Sample & Analyse


900a 5 300b


• 2 Key Principles – Value Adding (VA) – 55 minutes • Beneficial steps of the process, providing value to the customer


– Non Value Adding (NVA) – 1225 minutes • Process steps that provide no additional value to the customer


• Total process time of 1280 minutes (21hours) Process Cycle Efficiency (PCE) : 100xVA(min)/ Total Process Time(min) 100x55/1280 = 4.3% Table 1. Initial analysis of process steps for purification process


a Samples batched together for parallel evaporation, 12 – 15 hours overnight in a centrifugal evaporator b Samples reformatted, dried down into vials via parallel evaporation, up to 5 hours in a centrifugal evaporator


a daily consistent turnaround time that would easily align with weekly planning activities within the DMT cycle.


Managing these demands effectively, required critical analysis of each process step to understand its necessity, identify the time taken to complete and the value it provided from the perception of the customer. The outcome of this data analysis is represented in Table 1.


The high degree of inefficiency demonstrated by the PCE calculated in Table 1 strongly highlighted the need for improvement, prompting discussions to investigate the most effective way to reduce time taken to complete NVA (non-value adding) steps. It became necessary to identify causes and barriers influencing working practices, helping to understand why day to day procedures were conducted in a particular way. Continually questioning the nature and influence of these factors enabled detailed root cause analysis (RCA), establishing the underlying core reasons for the occurrence of individual problems. This concept of RCA was


demonstrated when evaluating the concerns over solvent evaporation, accounting for 97% of the wasted time, totaling 1225 minutes.


Compounds were routinely purified on an individual basis and then batched together for parallel evaporation. Following on from this, samples were reformatted into registration vials using organic solvent. Historically, these processes were used to overcome the continual lengthy removal of water from the numerous aqueous fractions produced during purification. Fundamentally, these aqueous fractions only occurred with the use of preparative HPLC, which due to its benefit was the preferred choice of technique within a purification service environment. Identifying this as the root cause of problematic evaporation provided opportunity to suggest and assess alternative methods of working. In particular, attention was focused on looking for appropriate alterations that provided large impact on time but that required the minimal amount of effort in terms of implementation. Specifically, emphasis on effort considered both the cost whilst attempting to avoid the


10 10


returned 5


Numerous ideas and suggestions were discussed focusing on alternative purification techniques and different methods of evaporation. Both of these avenues were explored extensively, providing five major suggestions for improvements, each varying in their approach. Alternative purification techniques such as normal phase flash silica or SFC were considered as they would avoid the utilisation of water, whilst the removal of water from fractions post purification using Fraction Trapping techniques


was also proposed. Alternatively, final discussions focused on answering two evaporation queries, could we routinely adopt a single rather than batch sample evaporation process and/or a method of evaporation from aqueous fraction straight into registration vials avoiding the time taken to reformat. The common use and availability of rotary evaporators provided the obvious answer for single sample processing, whilst for the second option the automated use of the vortex and vacuum technology was proposed.


Each of these proposals were ranked regarding the impact they provided on reducing turnaround time against the physical and financial effort required for effective implementation, summarised in Figure 2.


Evaluating potential improvements in this way simplified the most appropriate cause of action, with an ideal solution appearing in the top left corner of this diagram. Utilising the availability of spare rotary evaporators in- house was the most cost effective way to routinely achieve single sample evaporation.


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