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Changing Lanes


New drugs developed in the laboratory can often engage in processes which require the use of non-standard equipment or unusual environmental conditions. This trend is being driven by both market cost pressures and the need for pharmaceutical companies to find ways to address ageing drug portfolios. However, developing novel equipment and scaling up these new processes for full manufacture can be challenging and should not be underestimated.

Market Drivers

As the pressure increases on manufacturers to squeeze as much profi t as possible from existing drug portfolios, it is likely that companies will need to upgrade existing facilities in order to minimise costs. There is an opportunity here to introduce more automation and new technologies that can enable these cost reductions.

There has already been a move away from batch to continuous manufacturing, particularly as the industry becomes more comfortable with the application of regulatory requirements for such systems. Importantly, the continuous manufacturing approach is not only ideal for reducing costs for existing products, but may also be an important manufacturing option for lower volume, high value, niche products such as orphan drugs. It is these potentially high-value drugs to which pharmaceutical companies are turning their attention in response to the patent cliff.

The issues associated with the traditional blockbuster model have again been highlighted by the recent approval of Ranbaxy to launch a generic version of Lipitor in the US, and alternative therapies will become more attractive if novel processing systems can reduce the barriers to development and potentially make these niche drugs even more costeffective. As well as new drugs, alternative formulations or delivery technologies can also be introduced to extend the life of products beyond their existing patent lifetime. The need for more specialised equipment is therefore becoming more common, particularly when demands are lower and stability of input materials is critical.

Why Might Existing Equipment not Address the Market Need?

Typical pharmaceutical production equipment was primarily developed for well-known and understood products. When a drug was developed in the laboratory, scientists had free reign over the process steps and controls required to achieve the desired chemistries, unconstrained by existing production equipment and systems. Now, however, in order to realise the potential of a particular compound or to achieve a particular cost reduction, less conventional processes may be required. This could be particularly important for new drugs, which may be less stable or require production conditions that are unique or unusual.

Processing conditions could create a challenging production environment in several circumstances, including one or a combination of the following:

  • High or low temperatures
  • Low oxidation environment
  • High pressure or vacuum
  • Agitation
  • High energy reactions
  • Specific mixing or blending requirements
  • Low concentrations of active ingredients requiring novel dosing technologies

The attrition rate of medications in early clinical trials also means that manufacturing considerations at this point are often overlooked, as the effort would be wasted if the drug fails to progress through the development process. New equipment that accurately reflects the final production process and may have had only limited consideration up to this point may then be required within a rushed timeframe.

If the wide range of off-the-shelf equipment already available within the pharmaceutical processing industry does not meet the requirements of the laboratory process, how should a new piece of equipment or potentially a whole new system be developed?

Creating Solutions for Novel Production Processes

The approach to creating a solution for a novel production process will always depend on the exact circumstances, but broadly it should be the same whether a full system needs to be designed or if only a new part of an existing process needs to be implemented. The optimal route to a scaled-up system is to consider and follow the pertinent steps of a product or system development process, but with greater emphasis on the risk reducing activities for any new technologies. Ideally this development process should start as soon as possible, but in reality rapid development after Phase 2 clinical trials is necessary in order to ensure equipment representative of ultimate production is system-ready for Phase 3 trials.

The following sections outline the major steps that should be part of the development process and highlight the key areas which need to be focused on when considering novel equipment design and how this can reduce development time.

Concept Development

A good understanding of the laboratory process and system requirements is critical to the development and demonstration of suitable concepts. A vast amount of knowledge will have been gained from extensive testing and development in the laboratory, and this must be successfully transferred to the team investigating a scale-up process, so that the constraints of the fundamental science, physics and technology are understood. At this point it is important to challenge and determine if the laboratory process is indeed suitable for scale-up and what factors can be changed without affecting the product. A comparison with existing equipment can then be made to see if conventional equipment exists, or if there are similar processes used in parallel industries from which equipment can be adapted. For example, the food manufacturing industry has traditionally been faster moving compared to the more conservative and regulated pharmaceutical industry. Solutions may exist elsewhere which can be adapted for a GMP production system.

Where novel processes are needed, these can be broken down into discrete process steps so that concepts can be generated that meet requirements. These concepts can be evaluated for technical feasibility using modelling, analysis and simple experimentation, as well as suitability for a GMP environment. Once a concept with enough confidence has been selected, proof of principle test rigs can be produced. The proof-ofprinciple testing is the main risk reducing activity of this early phase of system development, as only by physically testing is it possible to explore the subtleties of a concept and whether the design will ultimately work. Proof-of-principle testing also provides invaluable information to the design team in terms of dimensions and parameters which can be adjusted.

Early evaluation of the laboratory process and proof-ofprinciple testing not only enable a design for a process module to be realised, but also allow the designer to accommodate other parts of the system or infrastructure more easily. It is this opportunity to combine and integrate the process steps that will ultimately lead to an efficient manufacturing system.

System and Detailed Design

Once the constraints of the existing equipment have been established and the first steps have been proven, they must be integrated into a consistent architecture. Combining the proofof- principle modules and existing off-the-shelf equipment needs a rational approach to the process architecture to create a robust production system. Bolting on standard pieces of kit without consideration of their limitations, requirements and interactions can lead to unnecessary and often very costly adaptors and mitigations later on in the development process.

At this point in a complex system development it is essential to understand the design implications that the laboratory process has on the critical quality attributes (CQAs), so that an optimised system architecture can be developed incorporating appropriate monitoring of critical process parameters (CPPs). This will enable the system designer to implement monitoring and controls accordingly, some of which may be purely for development purposes to increase knowledge around the process for scale-up optimisation. It is sometimes tempting to add as many sensors and controls as possible, but this should be exercised with some caution, as adding too many controls can unnecessarily increase qualification requirements. Complex integration of process analytical technology (PAT) is likely to be unrealistic at this stage if developing a pilot system in a short space of time, but may be necessary if incorporation of a sensor is a vital part of the process control. Careful consideration of system time constants will also influence the control approach. A long system time constant suggests a shift towards monitoring for a pilot system. For a production system where feedback control is desirable, the system may require the development of an expert system and knowledge base to deal with the uncertainty and long time delays. This will require additional development time, but can be based on information gained by testing the pilot system.

The physical layout of the system will need to consider any limitations of the manufacturing location. With 3D computer aided design (CAD) this can be achieved relatively easily providing that the manufacturing location is known in sufficient detail. Aside from size constraints, services and utilities may be more of an issue, but a pragmatic approach at the pilot stage can save a lot of time and effort. For example, it may be sufficient for certain materials, especially process liquids and gases, to be provided with appropriate certification from bulk suppliers.

Considering system and detailed design in light of the whole process will yield a consistent architecture which, if appropriate control and monitoring systems and infrastructure requirements are implemented, facilitates rapid and costeffective progress towards constructing a pilot system.

Prototype System for Pilot Production

The prototype system should be manufactured, assembled and tested according to a rigorous schedule to ensure that it meets the product requirements, and that all the system components are functioning correctly and integrated into the main system. Despite the proof of principle work, testing a full prototype system is likely to be the first time that all of the processes are run together. Prior to this, sub-systems will have been tested and commissioned separately, but it is only when everything is running together that all the interactions can be observed and understood. This is especially true for systems adopting a continuous production approach, as each section is dependent on output from the previous cell or module. Sampling at each process point may ultimately not be required on a final production system, but it is invaluable when developing a complex system with multiple and interacting sub-processes.

Development of Scale-up System for Commercialisation

A pilot production system takes the system development only so far. It is effectively a prototype which demonstrates the operating principles, in this case mass manufacture, that now must be optimised for full scale-production. As well as incorporating lessons and feedback from running the pilot system, the system will need to consider day-to-day operation more fully. Facilitating fast cleaning and setup procedures as well as process fluid recycling will require more consideration at this stage. This will depend on how far the pilot system was developed initially. It is also likely that the system architecture and design will need to be updated in order to maintain the process principles already established.

The operation of the pilot system also allows a good estimate of the cost of goods to be generated, highlighting areas where improvements will need to be made for the scale-up system. Waste reduction can create large savings and should be addressed as part of the system design.

The design, implementation and operation of the pilot system provides invaluable information and guidance for the scale-up system. Further development is likely to incorporate the additional functionality required for scale-up, but the fundamental novel processes should have been already proven and corresponding risks reduced.

Conclusion

Due to new market pressures, pharmaceutical companies may need to consider unusual manufacturing processes or environmental conditions that then require substantial equipment development. Although this task should not be underestimated, the challenges of the production environment can be overcome by innovation and early riskreducing proof-of-principle testing. Efficient investment in concept generation and proof-of-principle testing can make novel processes more commercially attractive, opening the door for new products to come to market. Rapid and robust development of new equipment and integrated systems is therefore possible in parallel with clinical trial timelines and in time for commercial manufacture.

As pharmaceutical companies move further into low volume, niche products, it is expected that there will be a much wider variety of drug products and custom variations aimed at addressing personalised medicines. These sorts of products will require highly flexible production facilities, capable of rapid changeovers, as introduced in the automotive industry, with principles such as single minute exchange of dies (SMED). Greater production flexibility will need to be considered far earlier in the pharmaceutical development process and will extend right to the end customer. Scenarios such as these suggest the requirement for the development of novel systems and equipment is likely to grow in the future and will require more agile, faster development programmes to keep pace with the drug development timelines.




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Matthew Chandler is a senior consultant with product and technology development consultancy, Sagentia Ltd. He joined the company in 2005 and has worked on a range of projects including development of novel pharmaceutical production systems for electrostatic coating of tablets and continuous manufacture of soft gel capsules. He has also been part of a Technology Strategy Board consortium project headed by GSK, investigating continuous tablet manufacturing with a system developed by GEA Pharma. Matthew has an MEng in Mechanical Engineering from the University of Bath.
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