QUALITY CONTROL - Life Cycle | Stick with Six

By Pedram Alaedini

Pharmaceutical Development and Life Cycle

The case for Lean Six Sigma in pharmaceutical formulation and process development

The evolution of the pharmaceutical industry has made product formulation, process development, and life cycle management more critical than ever. Expiring patents and the rise of generics, in addition to increasing drug development costs and regulatory requirements, are forcing pharmaceutical companies to develop products faster, cheaper, and better compared with just a few years ago.
Formulation and process development is one of the key—and at the same time most difficult and costly—segments in product development and commercialization. It is also one of the most critical functions, in which the future of a product, its potential success, the level of quality risks, and the strength of its patents, manufacturing capabilities, and customer satisfaction are determined.
For the development of products with good formulation and manufacturing processes in the least time possible at reasonable costs, the trial-and-error approach isn’t the best one—but shortcuts should be avoided. Indeed, the process of product development requires a systematic approach that ensures that only the right steps are taken, and in the most logical sequence.
With the increasingly competitive landscape of the industry, rapid and significant productivity improvements are becoming a prerequisite for every pharmaceutical company’s survival. Six Sigma tools and techniques, used in conjunction with methodologies common to Lean practice, have fostered a powerful performance system that has enabled noticeable productivity growth in other industries over the past few years. Indeed, Lean Six Sigma provides the basis for the strong complementary relationship that is shared by process, quality, and performance, a relationship that leads to sustainable competitive advantages.

The Trouble with Formulation and Process Development Projects

Usually, the objective of any pharmaceutical formulation or process development project is formulating robust products and introducing these products to the market quickly and within budget, while at the same time complying with regulatory and customer requirements. In addition, to be able to produce formulated products at commercial scales, processes must be easily scalable, allowing for a smooth handover from R&D to manufacturing groups.
Today, however, many formulation and product development projects suffer from a combination of problems that beget budget overruns, scale-up issues, time delays, and extreme frustration on the part of everyone involved. Most of these issues stem from:

• Lack of active involvement of top management and infrequent management reviews;
• Lack of required experience or talent assigned to projects;
• Unrealistic timelines;
• Poorly defined project scopes and goals;
• Lack of clarity regarding the activities required to achieve objectives;
• Lack of systems, basic infrastructure, and support from various departments; and;
• Inappropriate recognition and reward.

Formulation development is influenced by scientific, commercial, and regulatory factors in addition to intellectual property rights. Because of the complex technical and organizational challenges scientists encounter during formulation and process development, it is important to use an effective methodology during the development process that involves all stakeholders in an effective manner.

The Power of Lean Six Sigma

The ability to rapidly and effectively bring innovative and high quality products to market has become a hallmark of any successful consumer-driven enterprise. This is particularly true in the pharmaceutical industry, where radically shortened product development cycle times and drastically increased product quality levels remain the crucial differentiating factors between the best-performing companies and the rest of the industry. Speed to market is achieved by maximizing effectiveness in product formulation and process design and development, as well as in manufacturing stages.
Over the past 20 years in other industries and functional groups within the pharmaceutical industry, both Lean and Six Sigma methodologies have proven it is possible to achieve dramatic improvements in cost, quality, and time by focusing on process performance. Lean methods reduce waste, cycle time, and non-value added work, thereby improving information and material flow throughout the process. Six Sigma tools, on the other hand, are used to identify root causes of variation in processes, shift the process averages to optimal levels, and reduce variation around the average to find the best operating conditions, identify high-performance operating windows, and design robust products and processes.
Using either one of these methodologies by itself has limitations, however: Six Sigma will eliminate defects but will not address the question of how to optimize process flow, and Lean principles exclude the advanced statistical tools often required to achieve the process capabilities needed to be truly Lean. It is important, therefore, to understand how these two methods complement each other. And, while each approach can result in dramatic improvements, utilizing both methods simultaneously holds the promise of being able to address all types of process problems with the most appropriate toolkit. Lean Six Sigma is a systematic approach to redesigning business operations to minimize the waste (Lean) and variations (Sigma) that occur through process repetition.

In the context of formulation and process development, Lean Six Sigma can be used to develop product understanding and process controls prior to technology transfer to production and to further optimize the process at manufacturing facilities.

Implementing Lean Six Sigma

Lean Six Sigma applications in the pharmaceutical industry have so far focused on factory-based pharmaceutical manufacturing environments. Manufacturing dozens of batches of product is repetitive; minimal variation in output is a key goal. Consequently, savings realized from minimizing waste and cost through a coordinated Lean Six Sigma program across the manufacturing sites of a global pharmaceutical manufacturing company can be highly significant.
In recent years, there has been widespread interest in applying Lean Six Sigma approaches to pharmaceutical development activities because of the possibility that they could reduce waste, cost, cycle time, and variability in outputs. In the context of formulation and process development, Lean Six Sigma can be used to develop product understanding and process controls prior to technology transfer to production and to further optimize the process at commercial manufacturing facilities.
While product development is clearly a unique environment, the work performed across projects is similar and can benefit from some of the same optimization tools and methods that are applied to manufacturing. This is especially true for tasks that occur further downstream in the product development process, where manufacturing capability becomes an essential competitive advantage. It is possible to manage, standardize, and continuously improve the product development process as long as there is a solid understanding of, and allowances are made for, those characteristics of the product development environment that are indeed unique.
Obviously, there must be a balance. Not everything can be predicted through scientific analysis, but scientists must always work toward the goal of better product understanding during formulation and process development phases. Later in manufacturing, when the defects may be very easy to identify, they can be costly to correct. Conversely, in the early design phases, potential defects are more difficult to identify because of the need for predictive ability, but once defects are identified, they can be fairly easy to avoid.
Implementing Lean Six Sigma in pharmaceutical formulation and process development presents the same challenges as in other industries and functional groups and requires the same level of commitment on the part of senior management. In addition, in order to ensure proper execution, full-time dedicated champions must be assigned to assist in the implementation process.
In general, the principles forming the foundation for rapid and high quality formulation and process development teams, and the steps that constitute focal points that must be considered both in creating the development process and in managing formulation and process development projects, are:
Systematic approach to product development. The basic elements of the product development system—people, processes, and technology—must be fully integrated, aligned, and designed to be mutually supportive. With this in mind, the company must establish formal procedures for a streamlined process from pre-formulation to formulation design and development, through scale-up and technology transfer. This should also extend to support of manufacturing activities for a predetermined period. Indeed, Lean Sigma approaches are particularly appropriate for optimization of repetitive or routine activities such as checking and analyzing analytical data or batch defect rates.
Customer-first approach. The customer-first philosophy, both internal and external, results in a deep understanding of customer values and requirements, a necessary first step in any product development process. The customer for formulation and process development groups includes the patient, sales and marketing organizations, technology transfer and product support groups, manufacturing facilities, and perhaps many others.
Front-loaded process. Early scientific and engineering diligence and systematic problem solving and troubleshooting, along with true cross-functional participation, are the keys to maximizing the effectiveness of the product development process. Strong pre-formulation support to generate sufficient knowledge on active pharmaceutical ingredient properties, resulting in full understanding of potential development requirements, will be extremely beneficial through all future product development, manufacturing, and regulatory steps involved in approval and the commercialization process.
Continuous learning and improvement. Continuous learning and improvement for all involved must be a fundamental component of every job performed, rather than just a special one-time initiative.
Parallel and simultaneous execution. Concurrent scientific analysis and engineering force the formulation and process development teams to do the most they can with only the portion of the data and information that is available at any given time and is unlikely to change.
Standardization to create flexibility. Standardized skills and processes allow for program customization, broader scope of individual responsibility, a just-in-time human resource strategy, and flexible product development capacities. These standards are also crucial to downstream Lean manufacturing capabilities.
With the proper commitment and the correct approach, Lean Six Sigma will pay off significantly in terms of reduced development cycle times, higher product quality, reduced life cycle cost, and improved customer satisfaction. The only question now: Does a company have the dedication, over the long term, to challenge its scientists and engineers, openly view and address its weaknesses, understand its limitations, and eventually transform itself into a well-respected, world-class organization?