Ramping Up and Ensuring Supply Capability for Biopharmaceuticals

Stock outages of pharmaceutical and biological products occur with disappointing regularity.^1-2 Even newly launched products have not been immune, particularly biopharmaceuticals, which take longer to manufacture and require production operations that are more difficult to control.

One major pharmaceutical company faced supply challenges with two of its biopharmaceutical products and decided to take systematic action to ensure a reliable supply of patient-critical products. This company knew that one of the products was certain to be a blockbuster, creating demand that might outstrip supply. The other product, a monoclonal antibody, had already encountered supply problems. The company was determined to establish predictable manufacturing capability for both products and meet the challenge of enormous market demands, all whileensuring sustainable GMP compliance.

The company adopted a comprehensive approach to operational and organizational improvement thereby achieving better results than would have been attained by an exclusive focus on a single element (Figure 1). Because improving supply capability involves more than the physical plant, the company assessed all organizational and operational elements affecting supply: capacity, yield, reliability, documentation flow, cycle time, and other key performance parameters. They also designed a staff development and leadership program that stressed the importance of teamwork within the quality and operations organizations. These measures enabled the company to implement the comprehensive improvement program in just 12 months, strengthening the manufacturing capability of the operation, the flow of operational documents, the management reporting systems, and leadership ability.

Figure 1. Approach for rapid operational and compliance improvement.

Rapid Improvements

The supply capability of an organization depends on its ability to plan and execute not just the manufacture of product but also wider operations including process reliability, GMP compliance, effective leadership, clear communications, and operational metrics. To generate a targeted list of improvement opportunities in all these areas, the company first assessed a range of operational expertise including manufacturing and QA knowledge, operational metric design, organizational development, and statistical process control (SPC).

³

The initial target list was broad, ensuring no significant opportunities were missed (Figure 2). By uncovering common causes of the problems on the initial list, the project team was able to consolidate improvement opportunities into categories and further characterize them, aligning them with the overall goals and strategy of the organization and calculating the potential return on investment. Next, the team compiled a list of specific projects and formed cross-functional teams to address them. As the projects crossed functional lines, the teams employed were also cross-functional.

The assessment uncovered a number of gaps that impeded both the production ramp-up for the blockbuster drug and the consistent supply of the monoclonal antibody. These gaps included

• the need for 100% more manufacturing capacity to meet future demand for the blockbuster

• suboptimal manufacturing reliability for the monoclonal antibody, which stood at only 80% "Right First Time"

• inefficient processes for review of batch records, including review periods more than twice as long as necessary

• an inadequate measurement system for monitoring operational performance

• insufficient leadership and interpersonal skills for cross-functional teamwork inadequate training for production operators.

Figure 2. Elements of a comprehensive assessment.

Manufacturing Capability

Manufacturing capability depends on the interaction of three components - capacity, yield, and reliability (Figure 3). Understanding their interaction was critical to prioritizing improvement activities. Two manufacturing product teams, one for the blockbuster drug and one for the monoclonal antibody, were formed. To address capacity, the teams conducted a bottleneck analysis of equipment, people, and training constraints. As a result of the analysis, the team broke the bottlenecks by purchasing needed equipment such as additional storage vessels and refrigeration capacity, identifying the personnel required for production ramp-up, and cataloguing skill deficiencies - especially those in biopharmaceutical production, such as batch weighing, batch charging, chromatography, and GMPs. After identifying the needed skills, the team set up a training program to teach them.

To identify strategies for improving yield, the team applied SPC and multivariate analysis to historical production data; this method provides knowledge that cannot be derived from a few pilot, demonstration, or even validation runs.^4-5 For example, after the monoclonal antibody production team identified process shifts in fermentation yields, they formed a cause-and-effect team that included fermentation experts and a statistician. Using correlation tools and process knowledge, they identified two media components associated with a 30% shift in yields. The application of similar statistical and analytical techniques to other areas, including column chromatography performance and optimum column loading, resulted in higher reliability and a 10% improvement in yield. By identifying causes and effects, these techniques focus sharply on particular problems, thereby saving time and maximizing return.

Figure 3. Manufacturing capability model.

To address reliability, the teams analyzed historical process variances. A subset of the historical production data, variances are instances of "things that went wrong." These can include process control parameters that were not in control, changes to procedures, or any other variation from normal practice. Without process reliability, supply predictability remains impossible. Of course companies compensate for this unpredictability by adding manufacturing capacity- and incur additional costs. In the pharmaceutical industry, production variances and the resulting investigations pose the greatest threat to reliability and, in turn, supply capability.

The analysis of variances identified systems that were prone to problems - either mechanical problems, such as design and equipment suitability, or operational problems such as how the system was used. For example, repeated variances in the batch weighing process could reveal mechanical failures (such as inadequate scale design and installation suitability) as well as operational failures (which can include unskilled or inadequately trained operators and poor operating documentation). By uncovering root causes of variances, the team was able to strengthen both the mechanical and operational aspects of vulnerable systems. Most variance reduction programs fail because they do not uncover the root cause of variances, lack connection to a thorough system analysis, and poorly execute the corrective action. Given a poor definition of the problem and the lack of a system-level analysis, poor corrective action is inevitable.

Batch Record Review

Supply capability depends as critically on the flow of required documentation as it does on the flow of product. A cross-functional team of production and quality personnel constructed a process map of the batch record review process, detailing bottlenecks such as excessive time spent in the queue, an overly complicated flow of records, and a lack of clarity in the company's expectations of reviewers. The team collected baseline batch release data for both products and used fishbone diagram analysis to organize the defects of the batch record review process. They then used Pareto analysis to prioritize the correction of defects and control charts to measure the progress and impact of changes to the process.

As in most documentation processes, time for review is a major bottleneck. Through the use of a process map, the team established a framework for allocating the who, what, where, and when of review. This cut by half the time for batch record review. Not surprisingly, this had a significantly favorable one-time impact on inventory levels and costs, especially the monoclonal antibody with its longer cycle time. Better management of investigational reports for manufacturing variances and better design of the batch records themselves also improved cycle time.

Creating Metrics

Complicated biological operations require clear operational definitions and accurate and timely flow of information among shop floor, planning, and operations management personnel. For example, inconsistency concerning when a particular operation is considered complete can cause enormous confusion. A batch could be deemed "done" in a number of ways: when an operator finishes making the batch, when the documentation is reviewed, when Quality releases the batch, or when it is in inventory, ready for shipment. A month or more could elapse from the time something is

believed

to be done to when it

is

done.

Table 1. Critical metrics for the operational, quality, and compliance functions of the organization.

To establish relevant metrics, the team first reviewed the management goals of the operational, quality, and compliance functions to align them with the goals of the entire organization. Each metric was defined to ensure clarity regarding what was being measured and to ensure that it contributed to the desired outcome (Table 1).

The measurement system consisted of both a broad set of metrics called the "dashboard" and a lower set called the "manager's metrics." The broader, summary-oriented dashboard serves site management. The more targeted manager's metrics enable functional managers to gauge improvements in their respective areas. For example, the dashboard metric for batch-record release time indicates release times for the entire operation. The manager's metric, however, encompasses only the release times for the batch records in that manager's area. The measurement system immediately established a common understanding and communication of performance. Moreover, it provided a platform for improvement in numerous areas.

Training and Leadership

Major organizational change always requires training and leadership development, but the need was especially acute given the preparation for launching a blockbuster product. About 70 members of the quality and operations functions underwent training in such interpersonal skills as understanding people, expressing oneself, and resolving conflict -all critical for the smooth functioning of any organization with extremely complicated and highly interdependent processes. Approximately 95% reported they were "comfortable in applying the new skills." Forty people from that group received additional training in leadership, using case studies constructed from actual company experiences.

Members of the leadership group participated in an assessment of leadership knowledge, the results of which were compared to an extensive database and used to create ongoing leadership development plans. A significant amount of individualized and group coaching and ongoing assessment of the program's effectiveness supplemented the organizational development work. Participants reported "a common language and a shared understanding of concepts" that could be used in their day-to-day activities. Most importantly, this training ensured the thorough integration of the operational and organizational elements designed into the entire project at its inception.

Operator Training

Facing the need to produce greater volume with the launch of the blockbuster product, the project team undertook a detailed analysis of the manufacturing operation and its operators. A digital video camera recorded the actions of trained operators using both existing and revised standard operating procedures (SOPs) and batch record instructions for the operations. The videotapes provided both a model of appropriate behavior for operators and a forum for them to work together to develop best practices. In group meetings, experienced operators and process experts discussed and analyzed the operators' actions. Without the interference of shop floor noise, production gowns, or the fast pace of production, the training resulted in clearer SOPs and greater consistency of action from all operators - the operators themselves confirmed its effectiveness in their feedback.

Reaping the Rewards

The project team's efforts produced dramaticimprovements for both the blockbuster product and the monoclonal antibody. For the blockbuster, the breaking of bottlenecks increased capacity by more than 100%. Batch record review cycle time was reduced by 35%. Meanwhile, reliability improved in five manufacturing systems, including the maintenance system. SPC ensured the continued and accurate monitoring of critical process variables through the dashboard and manager's metrics. For the monoclonal antibody, the company attained 50% more capacity through optimized production scheduling: the proper sequencing and usage of equipment and utilities and the flexibility of operating personnel who were now trained to handle a variety of tasks. Statistical tools helped improve yield by 20%, and reliability improved in weighing systems and two other manufacturing systems. As with the blockbuster, SPC ensured continued monitoring.

Today, to monitor the improvements, the measurement system tracks 50 parameters covering the executive-level dashboard, including compliance, scheduling, training, and costs. The management-level dashboard operates in five functional areas, providing greater operational control and high visibility for corrective actions. At the same time, overall batch review cycle time has been reduced 60% through improved document flow, improved operator training, a redesigned batch record, and streamlined investigations. So these benefits are sustained, the process and structure are monitored and reinforced, ensuring the changes are taking root, operational and organizational improvements are becoming more integrated, and the improvement program's momentum is sustained.

Taking into account yield increases, a reduction in safety stock of 10%, material savings, and cost avoidance, the improvement of so many areas and systems produced a tenfold return on investment in the project. The real return, however, is even more significant. After the project, a much improved operating group exists with the confidence of the company to deliver on other challenging opportunities. The measure of that confidence? Following the successful launch of the blockbuster product, the biopharmaceutical group was cited for a global corporate award for their crucial role in the supply of the blockbuster.

References

1. Harris H. CDC warns vaccine supply is in jeopardy.

Wall Street Journal

2002 Feb 11.

2. Wechsler J. Safety, surveillance, and product shortages. Pharmaceutical Executive 2002 Jun.

3. Hoerl RW, Snee RD. Statistical thinking: improving business performance. Pacific Grove (CA): Duxbury Press; 2002.

4. Snee, RD, Hoerl RW. Leading six sigma: a step-by-step guide based on experience with GE and other six sigma companies. New York: FT Prentice Hall; 2002.

5. DePalma A. Bioprocessing - addressing process speed and optimization. Genetic Engineering News 2002 Dec.