Sample Preparation & Processing
Maximise productivity in pharmaceutical high-throughput experimentation (HTE) with automated powder dispensing
In the pharmaceutical industry, the pressure to reduce costs and increase effi ciency of drug development has fostered the growth of high throughput experimentation (HTE). This approach is only made possible by continuous developments and innovations in laboratory automation. HTE automation enables researchers to optimise route scouting and chemical development of new drug candidates, as well carry out solubility and stability screening more effi ciently. One of the major bottlenecks encountered in HTE workfl ows is the time and effort necessary to manually weigh and prepare all of the samples and reaction materials required. Dosing a defi ned amount of powder is an increasingly important task in pharmaceutical R&D. Consequently, accurate automated weighing of small quantities of powders could have a huge impact on the effi ciency of HTE workfl ows. Improvements in available technologies would benefi t drug development by enabling more rapid screening, reducing lead time for new treatments and, ultimately, improve patient outcomes.
High Throughput Experimentation Requirements
A typical HTE workfl ow is screening in chemical development, which allows for the rapid, parallel evaluation of a large number of variables in a timely and material-effi cient manner, and can be applied to both active pharmaceutical ingredient (API) and formulation (Drug Product) research.
A statistical Design of Experiments (DoE) approach minimises the number of experiments that have to be performed in order to investigate a process, whilst suffi ciently mapping the whole reaction space. This method is more effi cient and effective, allowing the optimal conditions to be identifi ed much faster, and at a much lower cost.
Figure 1: Optimisation of multiple parameters can be achieved simultaneously using a Design of Experiments (DoE) approach.
Screening and optimisation of reaction conditions is often carried out in 24, 48 or 96 vial plate format. It typically involves dispensing of 1 - 50 mg of multiple substances into each vial, according to a Design of Experiments (DoE) template, which can result in hundreds of doses being required to set up each experiment. There could be 20 different powder substances for each experimental design matrix.
Taking into account that some substances are particularly diffi cult to handle, and require dosing in small amounts (less than 10 mg) into vials of less than 8 mm diameter, it is clear that this task requires a great deal of time and concentration on the part of the researcher if this mundane and labour-intensive task is carried out manually with a spatula. However, for automated powder dispensing technology to successfully replace this tedious manual task, then it must be reliable, accurate, and easy for the laboratory researcher to use - not something requiring a highly-trained specialist user. Advances in automated powder dispensing technology would serve to increase R&D effi ciency, resulting in reduced lead time for new treatments, and benefi t patients and consumers alike.
Although the use of liquid handling automation is well-established in pharmaceutical laboratories, the development of automated powder dispensing has been much more challenging. Powder dispensing technologies have often been regarded as ‘complex’ and ‘specialist’, and some are only suitable for use with a limited range of powder types. Laboratory researchers have been put off by the fact that many commercial systems are complex to use, requiring hours of patient set-up and optimisation by a specialist for each powder, in order to achieve acceptable results. The wide range of physical properties exhibited by commonly used powders undoubtedly adds to the complexity of powder dispensing requirements for HTE. However, during the last decade, automated powder dispensing technologies are increasingly being integrated into pharmaceutical applications. These technologies have helped to increase research effi ciency and productivity, as well as facilitating advances in data integrity (by automatic recording of all dispense information) and enhanced safety and ergonomics for the research scientists (by minimising exposure to unknown potency substances and reducing repetitive manual tasks).
ETC ‘Collaborative Study on High-Throughput Powder Dispensing Systems’
A recent collaborative study of automated powder dispensing systems, carried out by the Enabling Technologies Consortium™ (ETC), has helped to position Quantos automated powder technology as the most reliable and versatile powder dispensing technology for laboratory applications, based on both accuracy for a wide range of substances and ease of general use. Set-up in 2015, the ETC is a group of thirteen major pharmaceutical and biotech companies who actively collaborate on chemistry-related issues. Their aim is to develop new enabling technologies for the benefi t of the pharma industry as a whole, working with 3rd parties such as vendors, universities and government labs where necessary. In this particular case, powder dispensing was identifi ed as a common bottleneck in pharmaceutical R&D, so a working group of fi ve leading pharmaceutical companies (GSK, Pfi zer, AstraZeneca, Merck, and BMS) initiated a benchmarking study. The goals of this study were to compare and assess the capabilities of existing commercially available powder dispensing systems, in order to identify any gaps in the technology, with a view to driving research and innovation to meet the HTE needs of pharmaceutical scientists, and infl uence the development of robust platforms.
Table 1: ETC powder dispensing study parameters. Test Substances:
Target weights:
• D-Mannitol • Fumed silica • L-Proline
• Limestone powder
• Polyvinylpolypyrrolidone (PVPP) • Sodium chloride • Thiamine HCl
• 2 mg
• 10 mg • 50 mg
Laboratory Environments:
• Fume hood • Glove box
• Local exhaust ventilation (LEV)
• Purge box • Open bench
Participating Companies:
• AstraZeneca • BMS
• GSK • Merck
• Pfi zer
The ETC automated powder dispensing benchmarking study involved four commercially available standard platforms, including the Mettler Toledo Quantos system. Seven reference substances were carefully selected which represent the range of challenging physical characteristics typically encountered in a pharmaceutical laboratory. These substances have varying fl owability, particle size and shape, density, and hygroscopicity properties. Over the course of the study, almost 18,000 data points were collected by the fi ve participating companies, in order to assess the accuracy and speed of dispensing powder into vials. Tests were carried out on each instrument, with
Figure 2: Quantos QH012- LNMP dosing head (2.5 mm diameter dosing pin with pushing stirrer and Pinocchio 1 mm nose, specifi cally designed for dispensing into small receptacles).
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