Single Pot

A mixer or granulator that dries granules in the same equipment without discharging
is commonly called a single pot (see Figure 1). The granulation is done in a normal
high shear processor; however, care must be taken to avoid the formation of lumps
as they cannot be broken down before drying. There are various options for drying in
single pots. The basic drying principle relies on the application of a vacuum in the
bowl, thus drastically lowering the evaporation temperature of the used granulation
liquid. The traditional heat source comes from the heated dryer walls. The heat
transfer is related to the surface area of the dryer walls and the volume of product
treated. Therefore, this direct heating method is most effective for small scale,
organic solvents or low quantities of binder fluids. The introduction of stripping gas
into the pot allows lower final moisture content to be achieved, which is only
required in some particular applications. A small quantity of gas is introduced in the
bottom of the equipment, which passes through the product bed, improving the
efficiency of vapour removal. However, as the heated wall is the only source of
drying energy, linear scale-up is not possible. This problem is exacerbated if:

 The material to be processed is heat sensitive (as this limits the wall
temperature)
 Water is used as a granulation liquid (it has a relatively high boiling
temperature under vacuum and a high heat of evaporation compared to
organic solvents)
 It is used for larger-scale production (the surface/volume ratio deteriorates as
the volume increases)

Microwave energy can be used to overcome these limitations. This provides a further
source of energy and has the additional advantage, with organic solvents, that only
pure organic vapours must be treated on the exhaust side, and not a mixture of
solvent and large volumes of process gas, as would be required in most other wet
granulation technologies.

Advantages: high containment, one-pot operation and a small footprint. The single
pot granulation process can compensate fluctuations in raw material specification. It
also boasts a very fast changeover and easy and safe handling of organic solvents,
as well as a high yield and a limited need of operators. Furthermore, it offers a
unique solution for effervescent production.
Disadvantages: limited throughput, no possibility for additional unit operations,
and difficult to scale up.

Single pot processing (one-pot processing) is a term that includes any technology that
combines different unit operations of a pharmaceutical production process into one
machine. Mostly however, one speaks about a single pot processor when talking about a
high-shear mixer-granulator that is also equipped with drying technologies. Thus, single
pot processing is the production of pharmaceutical granules using a wet granulation
process in which dry mixing, liquid addition, wet granulation, drying and sizing of the
granules is done in one machine. In the remainder of my answers, I'm taking this
definition as the starting point.

The benefits of this type of processing are:

  By integrating granulating and drying capabilities into a single unit, capital
investment in equipment and good manufacturing practice (GMP) floor space is
lower than other alternatives.
 The number of material handling steps is decreased: consequently, the total
processing time is shorter while maintaining a high yield and keeping production
support to a minimum. At the same time also the number of required operators is
reduced.
 Environmental variables, such as humidity, are eliminated from the
manufacturing process, which may offer advantages for processing moisture-
sensitive formulations.
 Requirements for solvent recovery systems are lower for single-pot processors
compared with fluid bed dryers.
 Reaching a high level of containment is easy by application of the correct
measures at in- and outlet valves.
 A single pot can be changed over in less than 2 hours, which makes it a very
attractive technology if a large number of different products- demanding a high
number of product changeovers- has to be produced. 

How prevalent is single pot processing in the pharmaceutical industry?

Single pot processing has always been a niche in the pharmaceutical industry, although in
recent years the interest has increased again because of the advantages it offers for the
production of highly potent compounds (Oncology medicines, hormones, etc.).

How may processes differ between different single pot systems? How do these
different processes compare in terms of advantages and limitations?

Single pot processors can be based on top- or bottom-driven high shear mixer-
granulators. The difference in the granulation process between a top- and bottom-driven
high shear granulator is not dramatic. Both types of granulators can produce high quality
granulates. Technically however, with top-driven machines the seals are outside the
product which can have GMP advantages.

The main difference between single pot systems lies in the drying technologies they offer.

The basic drying system for all single pot processors is vacuum drying (with heated bowl
walls to supply the necessary drying energy). The advantages of vacuum drying include
the low drying temperature and the ease of recovering the granulation liquid, as the
vapours are not diluted with air so can easily be recovered by condensation. This is
particularly advantageous when organic solvents are used for granulation: the emission of
organic solvent vapours is in most countries very restricted, and the vacuum drying
technology allows companies to comply easily with environmental regulations.
The main drawback of 'pure' vacuum drying is that the supply of drying energy is limited
to the surface of the bowl in contact with the product. For water-based products -
especially when producing large batches - this results in very long drying times at the
detriment of the granulate quality. 'Pure' vacuum drying is therefore mainly advised for
smaller batches and for solvent-based granulations).

Different options are available to complement the single pot processor to overcome the
drawback of 'pure' vacuum drying. Many manufacturers offer some type of gas stripping
during vacuum drying: a flow of inert gas is passed through the product during the drying
phase to enhance the drying process. Although the gas-stripping technology will help to
reach lower final moisture levels compared with vacuum drying, its effect on drying time
will not be dramatic, as the drying energy is still only supplied by the heated jacket of the
bowl so is still related to the available contact surface. This means that gas-stripping
technology is still only applicable for smaller, water-based batches. The technology is
also less suitable for solvent-based formulations as the vapours become diluted with non-
condensable gasses, which makes 100% recovery more difficult.

Finally, some manufacturers offer microwave drying on single pot processors. This is the
only technology that brings additional energy to the process, and thus will be capable of
significantly reducing the drying times. For water-based formulations, microwave drying
technology is certainly the method of choice if a single pot process is considered.
Another advantage of using microwaves during drying is that the temperature of the
jacket of the bowl can now be controlled as it is not required to supply the drying energy.
This means that there is a lot more freedom to optimize the yield of a process, as the
temperature of the jacket can be set at the correct temperature to avoid the product
sticking, without influencing the drying time.

The main drawback of microwave drying is that it is a relatively complex process and
requires both formulators and operators to have a good understanding of the process to
ensure that it is developed and executed correctly. Fortunately, all experienced
manufacturers of microwave equipment also offer extensive process support.

How have single pot processes improved and advanced during the last decade?

The first single pot processors were developed in the late '80s and the biggest advances in
process technology were made in the '90s with, for instance, the introduction of
microwaves.

In my opinion, the biggest advances in the field of single pot technology in the last
decade have been made in process control, containment and cleanability

As many new applications handle potent oncology medicines, the machines require
containment. This doesn't mean just the addition of high containment valves for loading
and discharging; it also requires there to be contained sampling when producing
validation batches or during production.
Cleaning in Place is an integral part of a good containment strategy that avoids any
contact between the operators and the product. Today systems are on the market with
validatable CIP systems.

What challenges remain to be overcome?

As for many technologies, the implementation of PAT is gradually becoming a given for
single pot processes. Nevertheless, there are still some challenges that need to be
overcome in this area related to reliability of the data capture (e.g. due to sticking of the
product) and the interpretation of the results.

The most advanced systems on the market now have a special PAT probe that can
monitor blend homogeneity, granulation liquid distribution, granulation end point and
humidity. The probe can be cleaned during the process to prevent the product from
sticking to the windows.

What regulatory considerations/hurdles must be overcome by companies wishing to

rep lace their current processing technology with single pot processing?

The regulatory hurdles to change to a single pot process are no different than when
changing to any other production method: SUPAC guidelines must be followed to
determine what level of change is represented by the switch to a single pot process. For
example: if the product is currently produced in a high-shear mixer and dried in a tray
dryer, the level of change for the unit operation of granulation will be level one as there is
no change in type of equipment (as a single pot processor is a high shear mixer). For the
drying unit operation, the change will be level two, but this would be the same if the
process was changed to a high shear-mixer - fluid bed dryer process as well.

One-pot processing is a term that includes any technology that combines different unit
operations of a pharmaceutical production process into one machine. In most cases,
however, a onepot processor refers to a high shear mixer–granulator that is also equipped
with drying technologies. Thus, onepot processing is the production of pharmaceutical
granules using a wet granulation process in which dry mixing, liquid addition, wet
granulation, drying and sizing of the granules is all performed in one machine.

The benefits of this type of processing are:

 By integrating granulating and drying capabilities into a single unit, capital

investment in equipment and GMP floor space is lower compared with other
alternatives.
 The number of material handling steps is decreased. Consequently, the total
processing time is shorter while maintaining a high yield and keeping production
 support to a minimum. At the same time, the number of required operators is also
reduced.
 Environmental variables, such as humidity, are eliminated from the
manufacturing process, which may offer advantages for processing moisture-
sensitive formulations.
 Requirements for solvent recovery systems are lower compared with fluid bed
dryers.
 Reaching a high level of containment is easy by application of the correct
measures at in and outlet valves.
 A single pot can be changed over in less than 2 hours, which makes it a very
attractive technology if a large number of different products demanding a high
number of product changeovers has to be produced.

Single pot processing has always been a niche technology in the pharma industry, but
interest has increased in recent years because of the advantages it offers for producing
highly potent compounds, such as oncology medicines and hormones. The concept of a
onepot processor in itself already ensures contained processing. Because all unit
operations are combined into one machine, the product is completely contained from
charging the raw materials up to discharging the dry granulate ready for compression. No
product transfers during the process are required, thus drastically reducing the exposure
risk. By applying the correct containment measures to loading and discharge valves, a
high level of containment is easily achieved.

Process variations

One-pot processors can be based on top or bottomdriven high shear mixer–granulators.

The difference in the granulation process between a top and bottomdriven high shear
granulator is not dramatic. With both types of granulator producing high quality
granulates. Technically, however, with top-driven machines, the seals are outside the
product, which can have GMP advantages.

The main difference between onepot systems lies in the drying technologies they offer.

The basic drying system for all onepot processors is vacuum drying (with heated bowl
walls to supply the necessary drying energy). The advantages of vacuum drying include
low drying temperature and ease of recovering the granulation liquid, as the vapours are
not diluted with air and can easily be recovered by condensation. This is particularly
advantageous when organic solvents are used for granulation; the emission of organic
solvent vapours is very restricted in most countries, but vacuum drying technology allows
companies to comply easily with environmental regulations.

The main drawback of 'pure' vacuum drying is that the supply of drying energy is limited
to the surface of the bowl in contact with the product. For water-based products,
especially when producing large batches, this results in long drying times at the detriment
of the granulate quality. 'Pure' vacuum drying is therefore mainly advised for smaller
batches and for solventbased granulations.
Different options are available to complement the single pot processor to help overcome
the drawback of 'pure' vacuum drying. Many manufacturers offer some type of gas
stripping during vacuum drying: a flow of inert gas is passed through the product during
the drying phase to enhance the process. Although gasstripping technology will help to
reach lower final moisture levels compared with vacuum drying, its effect on drying time
will not be dramatic because the drying energy is still only supplied by the heated jacket
of the bowl, so is still related to the available contact surface. This means that
gasstripping technology is still only applicable for smaller, water-based batches. The
technology is also less suitable for solventbased formulations because the vapours
become diluted with non-condensable gasses, which makes 100% recovery more
difficult.

Finally, some manufacturers offer microwave drying on single pot processors. This is the
only technology that brings additional energy to the process and is, thus, able to
significantly reduce drying times. For water-based formulations, microwave drying
technology is the method of choice if a single pot process is considered. Another
advantage of using microwaves during drying is that the temperature of the bowl jacket
can be controlled because it is not required to supply the drying energy. This means that
there is a lot more freedom to optimise the yield of a process, as the temperature of the
jacket can be set at the correct temperature to avoid product sticking, without influencing
the drying time.

The main drawback of microwave drying is that it is a relatively complex process, and
requires both formulators and operators to have a good understanding of the process to
ensure that it is developed and executed correctly. Fortunately, all experienced
manufacturers of microwave equipment also offer extensive process support.

Recent advances

The first onepot processors were developed in the late '80s, but the biggest advances in
process technology were made in the '90s with, for instance, the introduction of
microwaves. In my opinion, the biggest advances in the field of one-pot technology in the
last decade have been made in process control, containment and cleanability.

As many new applications handle potent oncology medicines, the machines require
containment. This doesn't just mean the addition of high containment valves for loading
and discharging; it also requires there to be contained sampling when producing
validation batches or during production.

CIP is an integral part of a good containment strategy that avoids any contact between the
operators and the product. Today, systems are on the market with validatable CIP.

As for many technologies, the implementation of PAT is gradually becoming a given for
onepot processes. Nevertheless, there are still some challenges that need to be overcome
in this area relating to reliability of the data capture (e.g., due to sticking of the product)
and the interpretation of the results.
The most advanced systems on the market now have a special PAT probe that can
monitor blend homogeneity, granulation liquid distribution, granulation endpoint and
humidity. The probe can be cleaned during the process to prevent the product from
sticking to the windows.

The regulatory hurdles to change to a one-pot process are no different to changing any
other production method: SUPAC guidelines must be followed to determine what level of
change is represented by the switch to a onepot process. For example, if the product is
currently produced in a high shear mixer and dried in a tray dryer, the level of change for
the unit operation of granulation will be level one because there is no change in the type
of equipment (a one-pot processor is a high shear mixer). For the drying unit operation,
the change will be level two, but this would be the same if the process was changed to a
high shear mixer–fluid bed dryer process.