By Paul Thomas, Senior Editor

Note: This is the third of four summaries written from a continuous manufacturing symposium at AAPS 2010 last week. The first two: FDA’s Christine Moore and U Washington’s Brian Marquardt.

It is often pointed out that “continuous manufacturing” is not actually new to the drug industry. After all, some say, unit operations such as milling and tabletting have been done in a continuous fashion for some time. Nevertheless, clearly more (and maybe all) of solid dosage manufacturing can be made continuous, and this was a premise of an AAPS 2010 talk by James Kraunsoe, PhD, of AstraZeneca R&D in Charnwood, UK.

Kraunsoe ackowledged that there have long been continuous components of batch processes, such as roller compaction, milling, and tabletting. Other aspects, such as wet granulation and drying, are just beginning to be understood in a continuous fashion, he noted, and technologies are being developed to execute them continuously.

Kraunsoe’s focus was granulation, and he showed video of a twin-screw high-shear granulator (from GEA Pharma Systems) being tested at his site. The equipment’s screw is made of transport as well as shear elements–they are modular in that “if you want more or less shear, you add or take away components.” He noted that the equipment can process up to 25 kilos of product per hour. “If you do the math, we can do a lot in a month or year,” he said.

From practical experience, Kraunsoe has found that process control is a significant challenge, but that experimentation can be done on the fly. “You switch the system on, it screws powder, adds water, and two seconds later you have granules. If you change the parameters, two seconds later you have different granules.”

Design of Experiments

Kraunsoe described the use of a placebo formulation to gain experience with Design of Experiment work. DoE is done “across the granulation design space.” The two main parameters considered were water amount and screw speed. Tweaking these factors, AstraZeneca did 11 experiments, one per minute. “So we’ve been able to visually, very quickly, map what our product looks like at these different parameters.”

Among the findings based on these experiments: First, he said, the amount of water used had a “significant effect” on granule and tablet properties, whereas screw speed was less significant. Secondly, the AstraZeneca team has “a high degree of confidence that we can replicate batch granule analysis using this system.”

In addition, he is confident that tablet quality will not be negatively impacted: “A range of continuous granulation operations exist which allows for a tablet quality that is at least equivalent of the batch processes.” He continued: “For both batch and continuous, you make some granules that can make quality tablets, and those that cannot. There is a large overlap between how batch and continuous do this, but the Quality by Design aspect of the project will allow us to gain increased understanding of the overlap.”

Concluding, Kraunsoe said:

• The “building blocks” for continuous tablet manufacture are available on the market—“not a lot, but some,” he said.
• Many unit operations are “inherently continuous.”
• Opportunities to adopt continuous processes “should build on a QbD approach.”
• These opportunities “need to be appreciated, evaluated, collaborated on, understood, and pursued!”

Finally, an audience member asked Kraunsoe the following question: Have you assessed how the variability of raw materials can impact continuous processes such as you have been doing?

His answer: “We have a lot of knowledge on the variability of API’s and excipients; we hope to eventually have a tool by which we can quickly assess how differences in raw material changes can be understood and accommodated . . . We haven’t assessed it, but fundamentally we think it will be easier to do.”

Note: Kraunsoe did not say how the anticipated closing of AZ’s Charnwood site in 2011 would affect the work described above. Here is the BBC report on that news from May 2010, and here is The Guardian‘s news item.

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