Lean Manufacturing practice in a cGMP environment

Developed in the 1950s as a means to survive and compete against the giants of the automotive sector, lean manufacturing helped Toyota evolve from a small-volume producer (with little capital) to become a high-volume manufacturer in a process-rich environment. Toyota achieved this by using developments such as total production maintenance (TPM), just-in-time (JIT), Kanban, value stream mapping and Kaizen events.¹ A summary of some of the lean terminology is shown in Table 1.

Table 1 Lean terminology

The pharmaceutical industry, manufacturing in a current good manufacturing practice (cGMP) environment, has been slow to adopt lean manufacturing — unlike many sectors where it has been successfully deployed. This article attempts to compare these two manufacturing environments and identify areas of overlap, together with challenges pharma may face in moving towards lean manufacturing.

Comparison of cGMP and lean

GMP has evolved gradually, however the recent scientific risk-based framework and the process analytical technology (PAT) initiatives, developed by regulatory authorities to support innovation and efficiency in a cGMP environment, suggest a new way of thinking for the 21st century.²

Since 2001, regulatory authority policies have promoted initiatives designed to increase the availability of new and affordable medicines. This new thinking should help the pharmaceutical industry move towards innovation in manufacturing and alleviate the fear of lean improvement. These fears will only be removed when manufacturers are confident that a successful lean implementation in a cGMP environment can have both regulatory approval and be technically dependable.

A comparison of cGMP with lean manufacturing (Table 2) might suggest that they belong to two conflicting families.

Table 2 A comparison of lean and GMP manufacturing.

While cGMP focuses on manufacturing as a means to produce safe and effective products for the patient, lean focuses on manufacturing as a location for improvement and value creation from a customer's perspective. For example, the public's expectation for an aspirin tablet has changed very little in comparison with their expectation for a personal computer during the last thirty years. They still expect the tablet to be safe and effective, while they expect the computer to have improved and provide greater value in return for the price paid.

Lean's dual objectives, to reduce or eliminate waste and to create value, differ from cGMP's objective, which is to ensure that controls are in place to deliver a safe and effective medicinal product. Perhaps where cGMP and lean do overlap is in a shared history in the control of the manufacturing environment. To see the degree of overlap, a new perspective of lean, referred to as lean pharma, will be discussed.

Lean pharma

Lean pharma can best be viewed by looking across the lean landscape from a cGMP perspective. To do this, one has to define in simple terms what "lean" means.

Lean landscape. In 1999, Spear and Bowen identified four rules that describe the make-up of the lean manufacturing system³

• Standard work — all work must be specified as to content, sequence, timing and outcomes.

• Clear relationships and communications — every internal customer-supplier connection must be direct with unambiguous ways to send requests and receive responses.

• Simple flow — the pathway for every product and service must be simple, direct and followed.

• Scientific method — improvement should be made using scientific methodology, under the guidance of a teacher and at the lowest possible level in the organization.

They identified the lean manufacturing paradox; the existence of rigidly documented processes that operate in a flexible and adaptable environment. It is the combination of being able to perform the simple things right, while also having the ability to change and adapt to customers' demands, which makes lean such a successful improvement methodology and business survival tool.

For the purpose of this article, it will be assumed that these four rules must be followed for a traditional manufacturing culture to reach the tipping point to transform into a lean manufacturing culture.

GMP perspective. One of the characteristics of a cGMP manufacturing environment is the abundance of documented processes such as standard operating procedures (SOPs), testing methods, environmental controls and training programmes. This documentation can be divided into technical standards and operational procedures.

Technical standards, such as product specifications, validated settings and production conditions, can only change following a change control exercise. Operational procedures, such as the way people interact with equipment and the way that product flows, are based on custom and experience, and will change regularly in response to deviation or safety concerns.

The essence of lean pharma is determining how current operational procedures can be modified to support short-term improvement, while maintaining the technical standards — thus ensuring no risk to the product. An attempt is made to do this, from a cGMP perspective, for each of the four rules defined here.

Rule 1: Standard work

Standard work in lean manufacturing is an agreed set of work procedures that establish the best and most reliable methods and sequences for each process and employee.⁴ It is a detailed instruction on how a task can best be performed today, with the understanding that it can be improved tomorrow.

Standard work procedures are communicated simply and easily; more chart and display than paragraphs and pages. The employees who work with the process write the standard work procedures and their descriptions reflect what actually happens in the work place rather than what might happen. It is written after the manufacturing step has been optimized to ensure product quality is reproducible and product flow is continuous.

Standard work is desired because if you can standardize a process then you can control it; and if you control it, then you can improve it. This is the essence of this rule.

In lean manufacturing, every step in every operation is performed in a predictable manner. The time, sequence, outcomes and inventory levels for each step are specified. The work time to perform a task is independent of the operator, so if it changes (increases or decreases) a problem has occurred. This immediately alerts the team leader to a problem as it happens, thus ensuring real–time control.

Looking at the pharmaceutical industry, it may appear that standard work is already in situ, with SOPs, manufacturing instructions, testing methods and validation protocols. However, these documents are often written by team leaders or scientists following validation and are only updated in response to a deviation, safety or quality issue.

In the cGMP environment, critical specifications and technical standards are very well defined, deviations from which are obvious and thus action can be taken. Operational procedures, however, are often light on detail and as a result, variations in these may not be detected. For example, the way an operator sets up a workstation may vary with respect to time and outcomes. A check sheet may ensure that critical steps have been completed, but the manner in which the end-result was achieved is not obvious. It is then possible for work variation to enter if people use slightly different methods to achieve the same result. Typical finished dose manufacturing instructions may include "charge the blender...", "set up take-off plate".

In a lean pharma plant, SOPs and other manufacturing instructions would be viewed as a means to expose problems and encourage improvement. Technical standards will be identified and fixed in line with regulatory requirements; all other operational procedures would be reviewed on a systematic basis and standardized with respect to time, sequence, content and outcome. For example, the batch manufacturing instruction could still contain the term "charge the blender", but the work standard for the blender would be written by the people who perform the action and would appear in a separate form, possibly as a chart or on-line display.

Key points

The challenge for the pharmaceutical industry in moving towards lean is to design new operational procedures that comply with all external regulatory requirements, but at the same time support continuous improvement.

Rule 2: Clear relationships

In the lean manufacturing environment, every customer-supplier connection is direct with unambiguous ways to communicate. There is a clear and agreed way to send requests and receive responses. Product and information flows from one department to another and the barriers between departments are reduced. The overall goal is to keep product flowing. Consistent cycle time is an indicator of good internal supplier-customer relationships.

In the cGMP environment, product cycle time is quality driven; it may take longer to release a batch than it does to produce it. Different departments usually have clear individual responsibilities and objectives. Departments often have separate responsibilities and objectives, resulting in teams working in isolation or in conflict with one another. Individual departments are often unaware of the impact that their delays or problems have on overall product flow.

In the lean pharma environment, cycle time and quality would be of equal importance. This overlaps with FDA's PAT framework of reducing production cycle time. When a deviation in cycle occurs, it may indicate potential quality issues. For example, if it typically takes an operator 40 minutes to set up a tablet press but a batch takes longer, this indicates a problem with that batch. In lean pharma, a request for help would be made by the operator at 41 minutes, thus commencing an investigation.

The need to ask for help when product flow is interrupted may lead to the identification of quality issues that otherwise might have been hidden from view or only detected during final release. For example, when an operator in a traditional pharma plant is required to produce a tablet to a specified disintegration time, the time it takes to set up the tablet press to produce tablets meeting the required technical standard is not controlled. In a lean pharma plant, the operator would have a work time standard. If it is not possible to produce the tablet to the required disintegration specification within this time, a call for help would be made. This may expose a problem in the upstream process, in this case granulation, which would otherwise be masked.

The challenge for pharma in moving towards lean is to reduce the grey zones of responsibility, slow response and late calls for help when problems occur, and move towards an environment where problems are immediately identified, shared and resolved across the plant.

Rule 3: Simple flow

In lean manufacturing, the pathway for every product and service must be simple and direct. Simple in that there is only one way to move forward and direct in that there are no loops, forks or fast paths.

In the cGMP environment, the product path tends to be direct but far from simple because of batch manufacturing. This batch production method is inherent in cGMP to prevent cross-contamination. Each process step usually has a holding time for work in process, thus encouraging intermittent flow. Typically, a pharmaceutical facility operates with surplus capacity to keep the product moving, rather than flowing; however, this operational mode obstructs simple flow. For example, when a batch of tablets is scheduled to run on a blister pack line and three lines are available, surplus capacity at packaging exists. This will hide the reasons for any excessive downtime and slow changeover on the lines.

Having available surplus capacity does not encourage continuous improvement or problem identification. From the customer's perspective, the fact that a pharmaceutical plant is running with surplus capacity should have little consequences in the short-term. The product will still be delivered on time, at the right quality and in accordance with cGMP, but the plant with surplus capacity available has higher operating costs.

In the lean pharma plant, product or services would not flow to the next available person or tool, but to a specified person or item of equipment. This rule enforces the economies of repetition — the more times you take a certain path the more familiar you are with that path. Each time the product takes the same path, an experiment will occur to uncover variation and expose problems. This encourages continuous learning over the life cycle of a product.

A batch moving from manufacturing to finished goods would only slow down for a value adding step. There would be a continuous programme to reduce batch queues and a move towards small-scale equipment to improve efficiency and manage variability. In lean pharma, the focus would be to reduce your batch size, move towards single unit flow, and thus improve responsiveness to changes in customers demand.

The challenge for pharma in moving towards lean is to introduce simple flow for products and services and expose areas where improvement in flow will reduce cycle time and cost. To move forward from batch manufacturing towards single unit flow.

Rule 4: Scientific improvement

The first three rules are rules of design, which show how to set up operations as experiments, with a view to controlling the process and ensuring it is reproducible. The fourth is the rule on improvement. Once you can do the job consistently every time, then you can improve. Attempting to improve a process that has too much variation often makes the process slower or reduce the effect of any improvements.

In lean manufacturing, the scientific methodology is the driving force to total quality. Without this, the manufacturing process is too variable and unstable to enable the introduction of a lean manufacturing philosophy.⁵

The cGMP environment is already rich in science. Science is used to develop the batch manufacturing process, support laboratory testing and evaluate product release to market. The employees who "handle" the product have a defined role, which is to produce product in a controlled and consistent manner.

Traditional improvements in the cGMP environment come out of reaction to deviation rather than from the need for variation reduction. The fear of change and the current systems to control it, together make continuous improvement very difficult. However, some pharmaceutical plants already operate with well-controlled and optimum processes. For these plants the move towards lean should not be such a challenge.

The challenge for the pharmaceutical industry in moving towards lean is to implement FDA's risk-based approach, which is firmly based on science and engineering principles.⁶

Conclusion

In a lean pharma manufacturing environment, cGMP and lean must be equal partners. The cGMP standards together with lean principles must be embedded into the culture of an organization and the business strategy must reflect this. This challenge is less problematic because of recent changes in regulatory thinking. The principles of FDA's PAT initiative appear to be extremely well aligned with lean manufacturing thinking, suggesting a positive outlook for lean pharma.

Anne Greene is a lecturer in pharmaceutical chemistry at the Dublin Institute of Technology (Ireland).

Dermot O'Rourke is a research student at the Dublin Institute of Technology (Ireland).

References

1. J.P Womack et al., The Machine that Changed the World (Rowson Associates, New York, NY, USA,1990) pp 51–53.

2. US Food and Drug Administration (5600 Fishers Lane, Rockville, MD 20857–0001, USA), Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, September 2004.

3. S. Spear and H. K. Bowen, Decoding the DNA of the Toyota Production System (Harvard Business Review, Boston, MA, USA, 1999).

4. Standard Work for the Shopfloor (Productivity Press, New York, NY, USA, 2002) p 6.

5. H. Thomas, Transforming the Pharma Industry: Lean Thinking Applied to the Pharmaceutical Manufacturing, Section 2, World Congress of Chemical Engineering (WCCE7), Glasgow, UK, July 2005.

6. US Food and Drug Administration (5600 Fishers Lane, Rockville, MD 20857–0001, USA), Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach, September 2004.