March 2009

Cover Story

If you build it in ...

Building quality into pharma, biotech innovates, regulates, stimulates


  • Economy hits pharma, biotech manufacturing processes.
  • Process technologies, designing in quality innovative processes.
  • Communication between process development, manufacturing key.
By Ellen Fussell Policastro



Process analytical technologies and quality by design are some of the key words pharmaceutical and biotech mavens use today as part of their daily vocabulary. "The fundamental point is not so much using the process analytical technology (PAT)," said Roddy Martin, vice president of industry strategy at AMR Research in Boston, Mass., "but the improvement of process performance as the basis of continuous improvement in the manufacturing process. The improvement of process performance lies in going back to the quality-by-design process rather than just looking at PAT as a capability; it's more fundamental than that."

Biotech moving faster

"If you look at biotech, they believe themselves to be much further along. And they are, strictly because real-time measurement in their processes has been online for a long time. It's the nature of their business," said Justin Neway, chief science officer at Aegis in Lafayette Col. "They have to do that because micro-organisms need to be coddled. In pharmaceuticals, that's less the case."

Applications for PAT

While companies such as Merck and Pfizer are seeing the benefits of PAT, it hasn't reached popularity in pharmaceuticals as much as in specialty chemicals, food, beverage and petrochemical said Alex Habib, an automation engineering consultant in Old Bridge, N.J.


Processes that would benefit from quality by design practices include fermentation and reaction, especially batch, Habib said. "Most of the pharmaceutical industry is batch in nature. So batch reaction centrifuge sees use in batch processes," he said. "It's almost like a washing machine where final drying spins off liquid before you actually put clothes in the drier. Centrifuge is a way to help with drying. Instead of heating it to dry, you first get rid of most of the liquid."

Jose C. Menezes, Ph.D., professor at Technical University of Lisbon, agrees biotech is forging ahead more quickly because bioprocesses are "strongly influenced by the quality of inocula and raw-materials used," he said in his paper, "The Use of PAT in Biomanufacturing," co-authored by Licinia O. Rodrigues, Ph.D., senior PAT specialist at 4Tune Engineering Ltd., and Arthur Voogd, Ph.D., product manager in pharma, at Yokogawa Europe BV.

"The number of parameters measured in a bioprocess are often only those related to what can be controlled (e.g., cell density, pH, extracellular concentration of substrates)," Menezes said. "Sampling frequency is conservative since those parameters are manipulated at a low frequency." As such, process development is time consuming and complex mainly because a large number of experiments must generate enough process knowledge out of possible combinations of variables involved (strain or cell lines used, raw-material conditioning and media formulation, inocula scale-up, and fermentation operation). "Finally, any PAT strategy developed for a dynamic process whose trajectory strongly depends on the starting conditions (e.g., inocula quality or previous development steps) must take into account information from previous processing stages if a precise end-point is to be achieved consistently," he said.


Process technology means to an end

During conferences and while visiting users, Neway has seen more and more a deeper understanding that PAT is a means to an end. "The end we're really all striving for is to have quality designed into our processes so variability is under better control internally," he said.

"Users don't care whether you understand your process or not. They care that you make safe, efficacious product that's available and affordable. If you need to understand your process more today to do that, fine. If you need to employ online instrumentation to obtain real-time control, fine. That's what you'll do. There was this evolution that we all need to be in PAT; then we all need to be in process understanding. It's all the same - a means to an end. The end is quality by design."

Real-time quality by design

Talecris, a manufacturer of blood fractions, factor 8, and other blood-clotting factors (proteins, complex molecules) uses highly purified water in their process, Neway said. "They aren't measuring proteins; they're measuring water because when you inject water, you can't introduce contaminants," he said. Before introducing this online instrument, they had to take samples and put them through lab tests that took days, Neway said. This left them open to potential contamination in samples. "Once they had validated the inline measurement of water quality, they eliminated all that time and had closed-loop control on water quality." The beauty of this process was its straightforward simplicity of measuring water quality using known, simple technology. "It wasn't a measurement of the product itself; it was a measurement they had introduced into the stream of one of the components of the processing steps. It was the water they were using in the process," Neway said.

Another instance of simple, straightforward process to build in quality is Pfizer's focus on the risk analysis portion of process development to try to understand what portions of the process would need the most development and attention, "because they were likely to be the largest sources variability and the outcomes," Neway said. "Again it didn't require fancy online instrumentation but a methodical examination of risks. It turned out that product didn't do well in the clinic, but they still published their work in risk analysis and the kind of thinking that's required to move toward real time and building quality by design."

Neway also referred to MerckSerono's approach, achieving lower variability in manufacturing by doing process development in a way that designs those processes to go into manufacturing better. "They've set up an on-demand data access and collaborative analytics environment that allows them to have their process development group move more quickly through development steps as well as collaborate with the manufacturing group," he said.

Regulatory freedom

The PAT initiative provides pharmaceutical manufacturers a certain level of freedom, said Dan Matlis, president Axendia, a life sciences strategic advisory company in Yardley, Pa. "In the traditional process, license holders have provided FDA detailed information regarding process equipment and parameters to be used for the manufacturing of a new drug product in the chemistry, manufacturing and controls (CMC) section of an application," he said. "Under this paradigm, changes in the manufacturing process for an approved drug may require review by FDA, a process that can be lengthy and tedious. As a result, manufacturers would often forgo changes to the process and get by with less-than-optimal processes.

"PAT requires a much deeper and mechanistic understanding of the product and the process," Matlis said. "With PAT, manufacturers submit process schematics as well as a characterization of critical product and process parameters. Rather than locking the specific steps and equipment to be used in manufacturing, PAT give companies freedom regarding the how of manufacturing, while focusing on ensuring tight processes that maximize product quality and minimizing costs. In a well-designed, PAT-based process, documenting compliance becomes a natural by-product of the process, rather than its primary focus," he said.

Communication key

Quite a few changes manufacturers submit to the FDA for approval could result from poor communication between the development team and manufacturing team, Neway said. "Merck Serono and GSK recognized quality by design starts in process development. You shouldn't be designing the process in manufacturing," he said. "What you do in process development must be transferred to manufacturing." This includes not just data, but knowledge and experience as well.




  2. Develop the process to see use in manufacturing

When people who have experience in biopharmaceuticals have to scramble to get data together from spreadsheets, it can slow submissions and getting approval. "If from day one you say 'my data matters, and everyone's working from the same data,' then putting the CMC together will be easier, take less time, and you've ended up with better science," Neway said. "But it's an ongoing operation. It has to be continuous, not episodic or crisis-based."



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