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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.
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
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
- High or low temperatures
- Low oxidation environment
- High pressure or vacuum
- 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.
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
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
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
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
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
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.
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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