Six σ :Future of Pharmaceutical Quality

Six sigma is a problem solving methodology which is centered around defect reduction and variation management. The term “Six Sigma” refers to a quality level wherein no more than 3.4 defects occur per million opportunities (3.4 ppm) as a result of product variation. In the pharmaceutical industries six sigma concept can be applied to improve the product quality and the reproducibility (in terms of quality) can be improved and chances of error can be reduced. The sigma sign is derived from the sigmoid shaped curves based upon the different percentage values obtained from a standard sigmoid curve different sigma rating are given accordingly. The deviation with respect to the average should be minimum to achieve the greater quality of product and less defective in product or service. Sir Bill Smith (the father of six sigma) embraces both continuous improvement and breakthrough performance. The sigma quality in the pharmaceutical process can be achieved by following the path which is

  1. Performance based regulation,
  2. Emerging new methods and technology which can enhance the process efficiency
  3. implementation of quality by design in new product or process development
  4. Continuous improvement and operational excellence.


Pharmaceutical Quality by Design (QbD) is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management (ICH Q8). Future of Pharmaceutical Quality Pharmaceutical QbD embarks upon systematic development of product(s) and process(es) with desired quality. As a patient-centric approach, the QbD philosophy primarily focuses on the safety of patients by developing drug products with improved quality and reduced manufacturing cost by planning quality at first place to avoid quality crisis. Beginning with pre-defined objectives, QbD reveals the pharmaceutical scientists with enhanced knowledge and understanding on the products and processes based on the sound science and quality risk management. Adoption of QbD principles, in particular, tends to unearth scientific minutiae during systematic product development and manufacturing process(es). Beginning with pre-defined objectives, QbD reveals the pharmaceutical scientists with enhanced knowledge and understanding on the products and processes based on the sound science and quality risk management. Adoption of QbD principles, in particular, tends to unearth scientific minutiae during systematic product development and manufacturing process(es). Amidst a multitude of plausible interactions of the drug substance with a plethora of functional and nonfunctional excipients and processes, adoption of systematic approaches lead to evolution of the breakthrough systems with minimal expenditure of time, developmental effort and cost. There are three levels of control strategy. A genuine QbD may play the most important role in assuring consistently high product quality and robust manufacturing, as quality differences can often be directly attributed to the difference in product and process design and development.

According to study from FDA suggested, owing to manufacturing disruptions 66% of drug shortages occur. These production disruptions are often due to the use of outdated manufacturing technologies and equipment for drug substance and drug product production. Though the type of equipment/technology and the reasons for being outdated may vary, new technology is generally important for improving consistency and efficiency in manufacturing. Accelerating the development and adoption of pharmaceutical manufacturing innovations, so-called “emerging technology,” is needed to realize the vision of six sigma quality. The FDA defined emerging technology as technology: (i) with the potential to modernize the body of knowledge associated with pharmaceutical development to support robust, predictable, and/or cost-effective processes or novel products and (ii) with which the FDA has limited review or inspection experience. Some relevant examples of emerging technology include continuous manufacturing of drug substance and drug product, “on-demand” manufacturing of drug products, use of robots in pharmaceutical manufacturing, 3D printed tablets, and new container and closure systems for injectable products. By continuously updating the technology or process being used the efficiency of the process can be improved and due to automatization in the process it is possible to reduce human interference so, the robustness of the process can be increased. The FDA’s process analytical technology (PAT) is a collaborative effort to introduce new and efficient manufacturing processes. Process Analytical Technology (PAT) is a system for designing, analysing and controlling pharmaceutical manufacturing processes through measurements of critical quality and performance attributes of raw and processed materials to ensure final product quality, the idea of which is to become more efficient while reducing over-processing, enhancing efficiency and minimizing waste. Also, continuous processing has a great deal of potential to address issues of agility flexibility, cost, and robustness. The pharmaceutical manufacturing sector is in transition, but overall processes are largely batch in nature.

Continuous improvement is a part of our overall effort to improve product quality, particularly for legacy products. Regulatory authorities need to create an environment and provide incentives for manufacturers to continually improve their manufacturing processes. A continuous improvement effort seeks to remove sources of inherent variability from the process operation conditions and raw material quality, resulting in higher process capability. Continuous improvement typically has five phases: (i) defining the problem and the project goals, (ii) measuring key aspects of the current process and collecting relevant data, (iii) analyzing the data to investigate and verify cause-and-effect relationships, (iv) improving or optimizing the current process based on data analysis (e.g., design of experiments), and (v) controlling the new process to ensure that any deviations are corrected. One company’s pursuit of quality reduced the error rate 96% from 2006 to 2014 and generated cumulative saving of $400 million. With respect to avoiding shortages and recalls, patients also directly benefit from this pursuit of excellence.

A regulatory approach that focuses on desired, measurable outcomes, rather than prescriptive processes, techniques, or procedures. Performance based regulation leads to defined results without specific direction regarding how those results are to be obtained. Interference of regulations can occur on any of the three phases of organization’s processes: the planning, acting, or output stages. Yu defined performance-based regulation as a regulatory approach that focuses on desired, measurable outcomes, rather than prescriptive processes, techniques, or procedures regarding how those results are to be obtained. At the Nuclear Regulatory Commission, for example, performance-based regulatory actions focus on identifying performance measures that ensure an adequate safety margin and offer incentives to improve safety without formal regulatory intervention by the agency. Pharmaceutical regulation should similarly be designed to improve the performance of individual and organizational behavior in ways that protect and promote public health, he said. This will machine learning, big data, and other Pharma 4.0 technologies that can measure and analyze processes in real time will further encourage performance-based regulation.

Integrated Six Sigma (Fusion management) is the answer to process perfection, overall quality assurance, the most efficient system for cost saving waste elimination and continual improvement of your product and services. “Admittedly, the industry has room for improvement in the adoption of six sigma principles,” but simple comparisons to other industries are unfair.” Consider, for instance, the relative ease of incremental change. The regulatory burden associated with process changes in pharmaceutical manufacturing is extremely high compared to that in other industries, which impedes motivation for continual improvement.