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Mar 1, 2011 (Vol. 31, No. 5)

CMOs Seek "the" Competitive Edge

Established Practices Like Lyophilization and Six Sigma Are Finding Novel Uses in Biotech

  • Contract manufacturers are embracing new uses of established techniques to give them an edge in an increasingly competitive environment, according to companies exhibiting at the “Interphex” conference later this month in New York City. Examples of such practices include lyophilization, single-use manufacturing, and established decision frameworks like Six Sigma.

    In some cases, the advances are being made slowly, balancing the gains with the extreme caution that is inherent in this industry. Six Sigma methodology is a case in point. It was developed in 1985 by Motorola to help it compete with Japanese telecommunications companies. Yet it is still working its way into biopharmaceutical companies.

    Baxter was one of the early adopters and has reaped the benefits for at least the past decade. A few years ago, when Baxter’s BioPharma Solutions business ran into difficulties with variability in a client’s project, it applied Six Sigma methodology to identify the problem and the solution.

    As Reuben Vandeventer, a DMAIC program manager at Baxter’s BioPharma Solutions facility in Bloomington, Illinois, recalls, “We had run some test batches but the process still yielded high particulate in the product vials, with no obvious reason. We executed a Six Sigma project, which uses a DMAIC progression (define, measure, analyze, implement, and control) as the central framework of the methodology. We found evidence of the problem and also how to solve it by using Six Sigma statistical analysis and problem solving.” That allowed Baxter to implement a control process that ensured the problem wouldn’t recur with that client or any other.

    “The remedy involved measuring the process by collecting and microscopically analyzing solution samples at the beginning, middle, and end of the filling process, measured in parts per milliliter. Those samples are compared in real-time against a historical control chart to determine the appropriate actions based on historical decisions associated with the control charts. Now, if particulate matter exceeds the parameters in that chart, action is taken,” Vandeventer says. Baxter also uses Six Sigma to improve its forecasting accuracy to stabilize variability.

    The Six Sigma approach is used by many industries concerned about process variability and instability. At Baxter, getting buy-in on the Six Sigma process begins with an internal marketing campaign that brands the project, generates excitement, and touts the successes.

    Vandeventer advises companies implementing a Six Sigma approach to identify “quick wins” in each project and go for those first. Then, once people see results, apply Six Sigma approaches to bigger, lengthier projects. “There are no silver bullets, and people need to be coached,” he stresses. Therefore, “you need someone with Six Sigma experience to be the champion.”

    “You also need training to minimize the pitfalls.” One of the key stumbling blocks, he says, is scope creep—trying to solve too much at one time. Another, is becoming derailed by an early setback. “Organizations get disappointed with results from the analysis phase,” if their basic assumptions are proven inaccurate.

    Although scientific data tends to be straightforward, business process improvement data is anything but, he emphasizes. “Look at the data. If it doesn’t make sense, tweak the study to ensure that it really is measuring the process you’re trying to improve.”

  • Quality by Design

    Ben Venue Laboratories applies quality by design methods to its lyophilization (freeze-drying)operations, “providing scientists with a more thorough understanding of the defined space to thereby develop the most robust and efficient lyophilization cycle possible,” according to Timothy McCoy, senior formulation scientist.

    “One of the advantages is that scientists can design the cycle around the defined critical process parameters to develop an optimal primary drying step, which is key to producing a robust product,” McCoy says. Ben Venue is also investigating ways to better control supercooling, using nucleation technology to lower the moisture content and create more homogeneous crystal structures.

    New technologies are also improving the development and manufacturing services, McCoy says. For example, “adding a sample thief to one of our development-scale lyophilizers enables us to accurately monitor moisture levels as a function of secondary drying conditions and time. That information is used to model and confirm the secondary drying stage of the cycle in one run.” That is particularly important with large, complex molecules to ensure that their activity is retained in the dried state.

    “We also have designed a new pilot plant with six development-scale lyophilizers representing bench-, mid-, and large-scale units, letting us confirm the performance of our developed lyophilization cycles at a comparable scale before entering cGMP manufacturing,” thus accelerating process development, McCoy adds.

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