PHARMACEUTICALS
‣ continuously operated pieces of processing equipment and new sets of reaction conditions , little progress has been made to establish the respective procedures to develop continuous processes and configure processing equipment in a fast , costeffective manner . As long as the development of a continuous process is seen as an addon to the conventional development trajectory , it also will be seen as timeconsuming and a means of last resort . Chemists will use these technologies too rarely to ever reach the operating skills comparable to those they have in batch processing . Indeed , developing a continuous process entails the development of a process plus dimensioning a plant instead of developing a process and then tweaking it to be operated in a given plant , a procedure many chemists are much more familiar with . This does not necessarily require extensive engineering , however . A well-designed apparatus will be easily re-configured and integrated into its plant environment . Typically , these are constructed as modules and have laboratory-scale equivalents used for process development or smallscale manufacturing . One more misconception about continuous processing may have hampered its adoption by CDMOs : the end-to-end continuous manufacturing process being seen as the holy grail of process development . Hardly any multi-step chemical synthesis will profit from such a concept in all steps . Instead , standard procedures to identify those unit operations that will deliver maximum benefit during scaleup if performed continuously include :
• Steps in which product quality depends on strict control of temperature , time , stoichiometry and mixing speed
• Steps that will limit production capacity , e . g . low temperature steps limited by cooling capacity
• Steps posing time bottlenecks , e . g . multiple extractions
• Steps posing volume bottlenecks , e . g . reactions requiring high dilution .
Continuous immediate diluent removal may help to both avoid large volumes of diluent and large volume equipment Clearly , continuous manufacturing steps must be combined with batch manufacturing steps to deliver maximum benefit and help staff to learn .
Standardise , standardise
To make scale-up a seamless process , the properties of continuously operated laboratory equipment must precisely model those of equivalent continuously operated pieces of plant equipment . The components of laboratory equipment must be quick to configure , combine and re-configure . Likewise , plant components must be re-configured and integrated into the existing plant quickly . Various equipment manufacturers offer such modular pieces of equipment for various unit operations of chemical synthesis , work-up included , and for form-giving . Standardised modular units may come with their own set of sensors using validation-ready analytical methods and a set of controls to ensure operation within defined limits . They may have standardised sequences of start-up , shutdown and operation , and come with predefined validated cleaning protocols and cleaning analytics . Next to their impact on process productivity and product quality , they will help to shorten product change-over , a typically rather time-consuming procedure in the CDMO industry .
Form-giving
As formulators enlarge their inventory of methods to provide medications with desired pharmacokinetic properties , the interface between chemical synthesis of an API and its formulation becomes critical , and advanced methods of both controlled isolation and formgiving of the solid API and analysis and understanding of solid state properties grow in importance . Since the majority of investigational new drugs ( INDs ) are solids under
Particle and powder properties have a significant influence on drug product manufacturing performance and should be defined and controlled during drug substance manufacturing
ambient conditions , crystallisation is still the dominant technology employed for isolation and purification , as well as for form-giving . Traditionally , the pharmaceutical industry has relied almost exclusively upon batch processes , accepting the frequently conflicting challenges stemming from the differences in scale-up behaviour of , for example , heat transfer and mixing . Continuous crystallisation has been the subject of intense research activity focused upon pharmaceutical development for close to two decades . While several long-term collaborative efforts between ethical pharmaceutical companies and academia have resulted in significant advances , the technology is still far from a routine application and has made little impact in the custom development business . 10-12 This may be due in part to continuous crystallisation processes being perceived as requiring processing equipment designed and built for a specific process and thus more suitable for bulk commodities . It may also be a result of the requirement for deeper understanding of compound-specific behaviour and the process parameters required to achieve a given target ( i . e . purity and
20 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981