Failure to get it right in designing and implementing a manufacturing process results in the loss of time and money, but the risk of this can be minimised if some basic organisational steps are followed, argues Brookwood's director of manufacturing.
An experienced team, a good understanding of the processes, an efficient monitoring system and attention to detail are crucial when moving from the production of clinical trial material to large scale manufacturing, Michael Hudson said in his speech at the Controlled Release Society's annual meeting in Vienna.
Although production in Phase I is development driven and in Phase II clinician driven, from Phase III onwards the complexities of large scale manufacturing and the demands of the market become important considerations in designing processes.
The first step on the road to successful scale-up is the assembling of a competent team. This involves all necessary groups, from project management and process engineering and chemistry to analytical chemistry and quality assurance. All these people must not just have a good track record but be able to work efficiently with members of different groups.
"Once you have put a team together, you then need to decide on the scale factor," said Hudson, who has led teams on multiple efforts for more than 90 lots of a variety of products and at a scale of up to 75Kg.
"You have to consider how much money you will lose if the batch is too big and fails and how much time you will lose if the batch does not fail but is too small - the most common choice is a factor of ten."
Then comes the drafting of a process flow document, a roadmap that captures all relevant specifications and developments of the product.
It describes the raw materials used, ensuring they are certified under good manufacturing practice (GMP) and that they can support large scale. It also outlines the unit operations, determining for example whether there will be standard mixing, blending or a novel step. Product specifications and process parameters, such as stir rates and temperatures, are also covered.
The document also addresses the selection of the equipment, an important aspect of the design since large scale usually leads to more process time.
The functionality, appropriate accuracy, sanitary design, its materials of construction as well as cycle time considerations are crucial in picking the right equipment.
Once all the infrastructure is in place, then control and automation has to be set up. This can involve stand-alone controllers (single or dual loop), process logic control (PLC), jacket temperature control and process fluid flow control.
"When you eventually try the process, you have to monitor everything, check if the samples meet your criteria and be quick to respond when failures occur," Hudson said.
"The active pharmaceutical ingredient (API) content is the most common criterion, so you look at the dispersion of the API, the emulsion and the final particle size, the amount of water there but you also care about the cycle time."
Nevertheless, even with these fundamentals in place, Hudson stressed that manufacturers should not be reluctant to outsource aspects of their production if they feel they lack know-how and equipment.