Open Batch Control: Not Quite Plug-and-Play, But Getting Closer

At May’s World Batch Forum, BMS and Pfizer discussed S88 and how they’re using it.

By Alan S. Brown, Contributing Editor

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To understand why batch manufacturers increasingly embrace open control standards, consider how to make a cake. The recipe might say to mix together the ingredients and bake at 350°F for an hour. Recipes always include materials and processing parameters (add, mix, pour) but rarely specify what brand of mixer or oven to use. Their universality is what makes them so easy to share.

No one would mistake baking a cake with synthesizing complex and highly purified pharmaceuticals. Making drugs requires pinpoint control, which is in turn highly dependent on the equipment processing them. Yet the cake analogy provides crucial insight into why pharmaceutical manufacturers are embracing the ISA S88 batch control standard: S88 separates the recipe—the materials and how to process them—from production equipment capability.

By adhering to the standard, users can write recipes without knowing anything about how their manufacturing equipment actually implements the recipe. Equally important, process equipment and control system vendors can integrate factories without knowing which specific recipes they will run.

S88 promises a quick, efficient and consistent way to run multiple recipes on a single batch line, or to run individual recipes on batch lines around the world. That, of course, is the theory. When it comes to any control technology, mastery of details determines how close anyone comes to achieving that goal. Last month, at the World Batch Forum annual meeting in Atlantic City, N.J., leading manufacturers shared insights and best practices regarding S88. This article discusses how Bristol-Myers Squibb and Pfizer are using open batch control to improve plant efficiencies.

BMS Pilot Plant Uses S88 for PAT
and to Harmonize U.S, Irish Plants

It was easy for the WBF attendees to sympathize with Paul F. McKenzie, executive director of process R&D at Bristol-Myers Squibb Co.’s New Brunswick, N.J., facility.

McKenzie’s scaleup facilities house 60 different reactors of various sizes and capabilities. They are used primarily to develop, study and optimize process routes for large-scale manufacturing. To do that effectively, McKenzie would like to use the S88 batch control standard to simplify the transfer of processing instructions to bulk manufacturing plants. He would also like to use plug-and-play process analytical technologies (PAT) to provide real-time feedback on process behavior.

Both goals, he told the audience at WBF, are works in progress.

Not just development

Both goals are worth achieving because the changing pharmaceutical regulatory environment has created a huge opportunity for companies that understand and master the science behind their manufacturing operations.

Until now, says McKenzie, Federal regulators have encouraged an industry manufacturing philosophy that could be summed up in two words: “Don’t change.” More recently, however, FDA has begun to encourage continuous improvement and risk-based assessment.

According to McKenzie, FDA sees two risk factors in pharmaceutical manufacturing. The first is a plant’s implementation of systems-based quality assurance and its regulatory track record. The second is its ability to fundamentally understand, monitor and control its manufacturing processes. FDA plans to reward companies that score well in these areas with less scrutiny, fewer inspections and reduced regulatory burden.

By using his scaleup facility as a test bed, McKenzie hopes to show how S88 recipe-based batch execution and plug-and-play and can improve flexibility, compliance and process understanding from the laboratory through the factory floor.

BMS has a roadmap to integrate relevant technologies into its operations. In the laboratory, it has embraced high-throughput process optimization, electronic notebook number crunching, and spectroscopic analysis. New Brunswick has put “a full-court press” on quality systems for materials, equipment, facilities and procedures. It bases its approach on International Conference on Harmonization (ICH) Q7A, which he calls "GMP in a reasonable format.”

Process control remains more problematic. BMS is already using Emerson’s PlantWeb to manage assets and S88 batch control and Fieldbus-based plug-and-play devices. It has begun to implement broader use of in-line PAT (which McKenzie redefines as “process assurance technology”). It plans to use the output to develop better processes and drive real-time process and predictive models. “Neither of those applications are there yet,” he concedes.

Harmonization saves

The attraction of S88, as mentioned, is that it enables manufacturers—at least theoretically—to run different recipes on the same equipment or clone existing recipes for use in new plants. S88 also provides a consistent way of thinking about processing. “The advantage of S88 is that it gives us a common vocabulary from the lab all the way up to manufacturing,” McKenzie explains. “The unit operations are really the same—heat, charge, distill—and we use S88 to leverage that commonality.”

McKenzie is putting S88 to the test by attempting to harmonize the New Brunswick pilot plant with a BMS manufacturing plant in Ireland. “Any application of S88 has to start with good equipment standards,” says McKenzie. “It’s very difficult between multiple plants, but an absolute necessity.”

At this point, he says, both facilities use consistent equipment PIDs and more than 125 standardized, validated S88 phases (devices grouped to perform a common function). “We have full electronic execution,” McKenzie says, including recipe execution on Emerson’s DeltaV, materials management on SAP, a common data historian, and real-time quality review reports delivered to the desktop.

“We did a back-of-the-envelope calculation,” he adds. “We estimated that harmonization saved us 7.5 man-years, 1,300 documents, and 7,800 signatures simply by reusing documents.”

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