MANUFACTURING

Applying Six Sigma and lean manufacturing principles in today’s risk-based regulatory environment

Bikash Chatterjee, President, Pharmatech Associates, Inc

The pharmaceutical and biotechnology market landscape has changed drastically over the last three years. Competitive pressures from the emergence of qualified, low-cost manufacturing capability for APIs and finished products in India and the portent of similar capability from China have challenged the status quo. Simultaneously the FDA’s shift to a risk-based approach for product development has changed the rules and expectations of manufacturers and regulatory authorities alike, compelling them to demonstrate that their processes and products are under control. The impact of these two “tectonic plates” has moved the threshold of change for US and European manufacturers who must attain unprecedented levels of efficiency to be competitive.

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Prior to 2002, regulatory oversight focused primarily upon adherence to pre-defined procedures, record keeping and audit trails. However, the realisation that a shift in the quality paradigm was necessary is evident on all regulatory fronts. The FDA’s objective in issuing its Pharmaceutical cGMPs for the 21st century guidance in 2004 was to propose a more scientifically rigorous system, integrating quality, safety and risk-management considerations.

The FDA did not work alone: it enlisted input from regulatory bodies in Canada, Europe and Japan, as well as industry and academia globally. At the centre of this worldwide mindset shift are several key guidance documents from The International Conference on Harmonisation (ICH), ICH Q8 (Pharmaceutical Development), ICH Q9 (Quality Risk Management) and the forthcoming ICH Q10 (Quality Management). ICH Q8 articulated a more scientific framework for process and product development, termed Quality by Design (QbD), which focused upon understanding which key drivers affect process stability and ultimately product performance, rather than quality oversight. ICH Q9 defined a methodology for assessing, mitigating and controlling risk to present the industry with the opportunity to concentrate their quality efforts on only those elements that matter. ICH Q10, still under review, attempts to describe a method for integrating ICH Q8 and Q9 requirements into our quality management systems. Together these form the foundation for a new approach to drug development and quality.

While no simple solution can transform an organisation’s effectiveness overnight, there are methodologies that specifically affect this type of industry transition. Operational excellence approaches such as Six Sigma™ and lean manufacturing both provide a framework for pharmaceutical organisations to realign themselves with this new mindset. They share several common elements indicative of systems that are successful in changing organisational thinking:

Structured methodology: measurable milestones;
Data-driven decision making;
Risk-based optimisation techniques;
Cross-functional effort.

This article describes the basic elements of Six Sigma and lean manufacturing and characterises the considerations necessary to apply them effectively in today’s risk-based regulatory environment.

Six Sigma Roadmap

The Six Sigma roadmap is a methodology for improving business processes, increasing customer satisfaction, and elevating business competitiveness. It establishes guidelines for creating the right organisational support structure to enable business improvement using structured project prioritisation as a backbone, and a fact-based, data-driven process for making sound business decisions. Recognising that all processes wander, Six Sigma focuses upon identifying, eliminating and controlling those elements that introduce unexpected variation into a process. It is these contributors to variation that jeopardise process predictability and, ultimately, product performance. The Six Sigma roadmap uses a five-phase project management process to drive improvement: Define, Measure, Analyse, Improve and Control (DMAIC).

Each phase in the DMAIC process is intended to guide the members of an improvement team through the project in a way that provides the right data and best process understanding. The DMAIC project management approach allows the business to make the best possible decisions with the available data and resources. The concept behind the five-phase DMAIC process is as follows:

Define: Clearly define the problem and relate it to customer needs.
Measure: Measure what is key to the customer and know that the measure is accurate.
Analyse: Search for the root causes and identify the most likely causes.
Improve: Determine the root causes and establish methods to control them.
Control: Monitor and make sure the problem does not come back.

Within each of the DMAIC phases there are a set of deliverables that must be completed to ensure all project requirements are met. A summary of the deliverables and typical activities for each phase of the DMAIC process is shown below in Table A.

Six Sigma involves creating the right organisational support structure. Key to this structure is the selection of both dedicated and part-time resources to support the improvement effort. If the proper resources cannot be allocated, it is doubtful that the Six Sigma initiative will yield the desired level of success. The roles and responsibilities of each individual in a Six Sigma deployment effort are shown in Figure 1.

Lean Manufacturing

Unlike Six Sigma projects, Lean projects focus upon efficiency. Founded by Taiichi Ono at Toyota, the science of lean manufacturing revolves around identifying those tasks which bring value to the customer, and eliminating, where possible, all activities that do not add value. Lean principles do not require statistical analysis, rather they rely on a simple set of tools to address inefficiencies within an operation. For this reason, lean tools are often the first to be implemented within the pharmaceutical environment since they are much more accessible to organisations that are just beginning the road to organisational change. The tools within the House of Lean are shown left in Figure 2.

Lean principles attempt to align process productivity with market demand, striving to eliminate finished goods inventory. Tools within the Lean toolkit include:

Quality, cost, delivery
Shorten production flow by eliminating waste Just-in-time
The right part at the right time in the right amount
Continuous flow
Pull systems
Level production
Built-in quality
Error proofing – Poka Yoke
5S, Visual controls
Operational stability
Standardised work
Robust products and processes
Total productive maintenance.

Lean applies these tools within the context of a rapid problem-solving framework—called a Kaizen—to realise improvements in efficiency and subsequently, cost reduction in five to 10 days. This short-term timeframe is one of the key reasons pharma has embraced lean principles as a key component of their continuous improvement initiatives. Within the industry it is not unusual to realize 30-80% increases in plant capacity, increased overall equipment effectiveness, reduced labour costs and greater overall process predictability.

Six Sigma and Lean Drivers

The incentives to pursue Six Sigma and lean are many fold. Drivers for moving toward a data-driven basis for product development and operating efficiency vary within the industry. Publicly traded companies face the challenge of escalating corporate performance expectations on a regular basis. Borrowing a page from the semiconductor and automotive industries that have successfully applied these methodologies seems logical if pharmaceutical companies are to successfully transform their development, operations and quality organizations to meet the expectations of the new risk-based regulatory environment. Applying Lean Six Sigma principles early in the drug development process affords the possibility of significantly lowering the cost of product scale-up and technology transfer, while also reducing time to market. Contract manufacturing organisations (CMOs) feeling the pinch from overseas competition look to Six Sigma and lean to reduce the variability within their operations.

Despite the lure of low-cost manufacturing and clinical trial costs, this is a quality-driven industry. Cost of poor quality (COPQ) remains a key component of the industry’s strategic planning. The learning curve associated with making pharmaceutical products is significant. If CMOs can improve their competitiveness through increased efficiency and increased process predictability driving down COPQ, then they can realistically compete with low-cost producers from the Far East. Conversely, low-cost manufacturers in the Far East need to climb the learning curve quickly if they are to get a toehold against the competition. Establishing their quality and compliance infrastructure along with embracing lean Six Sigma principles will help them maintain their costcompetitive advantage and allow them to compete from a quality level in the global—and most importantly— in the US marketplace.

Conclusion

Applying lean and Six Sigma principles to improve process predictability is an efficient and effective means of being competitive in today’s regulatory environment. The integration of risk-based management tools, coupled with a measurable framework for process understanding are the two basic tenets of the FDA’s regulatory expectations. QbD can be achieved successfully through the application of the DMAIC roadmap and it is highly effective, particularly in its ability to focus an organisation on a clear business need and to define a tactical path to resolution. Finally, whoever is able to leverage the principles of lean and Six Sigma will be positioned to move their organisations forward in this new, risk-based marketplace.

™ Six Sigma is a registered trademark of the Motorola Corporation

Bikash Chatterjee

Mr. Chatterjee has served in various senior management positions within the pharmaceutical, medical device/diagnostic over the last 25 years and is a frequent lecturer and instructor regarding Lean and Six Sigma practices in the regulated life sciences industry

Mr. Chatterjee is a certified ISO 9000 Lead Assessor and Six-Sigma Master Black Belt. Mr. Chatterjee has extensive experience in the design and implementation of quality systems and has successfully implemented six-sigma and lean manufacturing solutions in the biotech, pharmaceutical, cosmetic and food industries for over 15 years. TechSolve has managed and successfully deployed Lean and Six Sigma initiatives for both large and small pharmaceutical and biotech customers. Mr. Chatterjee holds a B.A. in Biochemistry and a B.S. in Chemical Engineering from the University of California at San Diego.

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