Moving From Batch to Continuous: Striving For Greater Efficiency in Pharmaceutical Manufacture
Yogin Chandorkar, Assistant General Manager, Aimil Limited
Jamie Clayton, Operations Director, Freeman Technology

Across the pharmaceutical industry there is a pressing need for greater manufacturing efficiency. This article considers the potential benefits of continuous processing as well as the tools that can help to achieve success .

The benefits of continuous manufacturing justify significant investment as evidenced by collaborations such as the MIT/Novartis Center for Continuous Manufacture. Batch production currently dominates within the pharmaceutical industry but within 20 years many expect that continuous processing will secure a substantial share of manufacture.

This article discusses the benefits of continuous manufacture and considers how analytical practices may need to change to support new manufacturing models, highlighting the need for techniques that support intelligent processing. Dynamic powder testing is introduced as a method which can contribute to the development of efficient continuous processes.

Exploring the Benefits of Continuous Manufacture
Although innovative in terms of drug discovery, and at the forefront of fundamental research, the pharmaceutical industry has historically focussed less on processing. Patent protection previously ensured that R & D costs could be properly recouped but as those costs rise, and times to market increase, this is no longer guaranteed. Once patents expire, profitability relies on efficient production, making this a focus for the industry. Furthermore, the regulatory focus on risk suggests a need for greater understanding of manufacturing processes and improved control of product quality. A shift from batch processes that are heavily reliant on manual intervention to automated, continuous operation is highly attractive.

In batch production, sequential process steps are undertaken, with analysis performed between each one to determine success. Batch-to-batch variability and products outside the defined specifications are common problems. The associated re-work required and level of waste are considered unacceptably high.

Continuous processing is widely used in industries such as chemicals and foods and offers several important advantages:
• Reduced costs
• Less waste
• Improved asset utilization
• Simplified scale-up
• Better containment
• Labor savings
• Lower capital investment

These highlight the environmental, safety and economic improvements that continuous operation brings but there are also technical benefits.

A batch step has a beginning and an end; between these points the product continuously changes, e.g. a blending process starts with the unmixed constituents and proceeds to an appropriately homogeneous state. A well -controlled continuous process should operate at steady-state for the majority of the time which requires effective process monitoring, as exemplified by widely used techniques such as in-line particle size and near infrared (NIR) analysis. Steadystate operation means that continuous processing is associated with consistent output which equates to more assured product quality with less re-work or waste. Scale-up is also simplified as production targets can be met by running smaller units for longer avoiding the complications introduced by changes in equipment geometry and material volume.

It is also important to consider the benefits of batch production. One advantage is flexibility, as a suite of batch equipment can be easily re -configured for different products. Batch production also simplifies isolation and containment of a problem. With continuous manufacture, there is a question of how to define a 'batch'. A batch essentially becomes associated with an operating period which begins when startup completes and the product is being manufactured successfully, and ends at a defined point. Any out of specification products are therefore associated with a time period rather than a discrete batch number which can make problems difficult to isolate and rectify.

Optimised processing, whether batch or continuous, relies on a comprehensive understanding and control of the materials and process variables that define clinical efficacy. The pharmaceutical industry has traditionally focused on developing and adhering to repeatable processes. This approach relies on consistent feed and provides little flexibility to respond to variation. This is a critical limitation as feed variability is a major source of failure so there is a desire to move from empirical batch processing towards knowledgebased continuous manufacture. However, there are challenges associated with this transition.

An Analytical Toolkit to Support More Efficient Manufacture Widely employed operations, such as milling, roller compaction and tableting, can be considered semi-continuous, as they are constantly fed during a batch campaign. The challenge involves engineering the equipment for reliable, prolonged operation and successfully integrating the necessary components into an optimized continuous process. Automation is important but so are analytical tools that provide the necessary knowledge to optimise multicomponent systems, such as information on powder flow, compressibility and other material characteristics. The Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) is one of the groups at the forefront of research in this area. Working to develop a test bed for the production of solid dosage forms, the group applies modelling skills, in -line analysis and techniques such as powder rheology, to integrate sequential blending, dry granulation, lubrication, and tableting. A key focus is to develop solutions that avoid three common issues that compromise the quality of batch produced tablets: segregation, agglomeration and compaction quality [2].

Whether improving batch processing, or introducing procedures to design, monitor and control continuous manufacturing, the industry needs appropriate analytical tools that deliver process relevant data and expand understanding of how processes work and can be improved, reinforcing the FDA's Process Analytical Technology(PAT) initiative. There are two strands to analytical requirements. Firstly, a need for techniques that provides process relevant information that help achieve efficient and reliable continuous production. Secondly, a requirement for intelligent and relevant approaches to process monitoring and control.

PAT has become synonymous with realtime analysis but the initiative is much broader. The FDA defines PAT as 'a system for designing, analysing and controlling manufacturing through timely measurement (i.e. during processing ) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.' Real-time analysis is therefore important but so are techniques that, for example, provide robust analysis of feeds prior to introduction to the plant , or the use of soft sensors [3]. Focusing on information required to achieve process efficiency and identifying techniques that provide it is a pragmatic approach.

Focusing on Powder Testing
Tablets are the most common drug delivery vehicle and the majority of drugs are handled in solid form at some point during manufacture so this brings attention to suitable analytical tools for powder testing. Numerous methods have been developed to characterize powders including angle of repose, flow through an orifice and tapped density. These techniques are relatively simple and provide some insight into the nature of a powder. However, the need for accurate, process relevant data exposes limitations and highlights the merits of methods such as dynamic testing.

In dynamic testing, axial and rotational forces acting on a blade are measured as it rotates through a powder sample to determine values of flow energy which directly quantify how easily a powder flows under conditions that reflect processing environments. Powders can be characterized in consolidated, conditioned, aerated or even fluidized states, to measure the response to stress and air content. The impact of moisture, flow additives, prolonged compaction, attrition and segregation can be directly assessed.

Figure 1 contrasts the change in bulk density induced by tapping with the corresponding change in flow energy. The flow energy increases by an order of magnitude greater than the density suggesting that flow energy measurements are significantly more sensitive in detecting the impact of a change. Furthermore, this indicates that tapped density could be misleading in terms of quantifying how consolidation might impact a process.

This experiment emphasises the importance of selecting a suitable analytical technique for a given application. It is increasingly acknowledged that no single powder testing method is ideal for every application but that a test should represent the conditions that the material will be exposed to.

Shear testing, for example, is a wellestablished technique that was developed to support hopper design protocols. It is still applied in this arena, with modern instrumentation delivering improved reproducibility, and is a valuable tool for characterising powders in a static, consolidated state but there are limitations.

Figure 2 shows shear and flow energy data for two common excipients, vanillin and ethyl vanillin. Shear testing characterizes these materials as identical while dynamic testing indicates varying properties. As the flow energy measurements demonstrated correlation with in-process behavior, these results indicate that materials classified as identical by shear testing may actually process differently. This highlights the importance of employing a method that closely simulates the conditions in a given process.

Looking Ahead
The rise of continuous manufacture, and the associated drive for greater processing efficiency, increases the need for relevant analytical techniques that support intelligent process design and enable effective process monitoring and control. It is essential to consider what information is required and identify how best to obtain it. Applying this approach to powder characterisation highlights limitations with traditional techniques. Innovative techniques such as dynamic testing and in particular, instruments that combine dynamic testing with other methods such as shear and bulk property analysis, present an efficient and versatile choice for those driving pharmaceutical processing to new levels of efficiency.

References:
  1. Reuters, "Drugmakers warn of $140 billion patent 'cliff'" (2007). http://uk.reuters.com/article/idUKGRI22300720070502
  2. Test bed 1 plan from the C – SOPS website. http://ercforsops.org/ Display/ General.aspx?CategoryId=11
  3. N. C. Chakrabarti ‘Virtual sensors for advanced pharmaceutical control’ http://www.pharmamanufacturing.com/ articles/2006/063.html