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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 e ta!en to avoid the "ormation o" lumps as they cannot e ro!en down e"ore drying. There are various options "or drying in single pots. The asic drying principle relies on the application o" a vacuum in the owl, thus drastically lowering the evaporation temperature o" the used granulation liquid. The traditional heat source comes "rom the heated dryer walls. The heat trans"er is related to the sur"ace area o" the dryer walls and the volume o" product treated. There"ore, this direct heating method is most e""ective "or small scale, organic solvents or low quantities o" inder "luids. The introduction o" stripping gas into the pot allows lower "inal moisture content to e achieved, which is only required in some particular applications. A small quantity o" gas is introduced in the ottom o" the equipment, which passes through the product ed, improving the e""iciency o" vapour removal. #owever, as the heated wall is the only source o" drying energy, linear scale$up is not possi le. This pro lem is exacer ated i"% The material to e processed is heat sensitive (as this limits the wall temperature) &ater is used as a granulation liquid (it has a relatively high oiling temperature under vacuum and a high heat o" evaporation compared to organic solvents) 't is used "or larger$scale production (the sur"ace(volume ratio deteriorates as the volume increases)

)icrowave energy can e used to overcome these limitations. This provides a "urther source o" energy and has the additional advantage, with organic solvents, that only pure organic vapours must e treated on the exhaust side, and not a mixture o" solvent and large volumes o" process gas, as would e required in most other wet granulation technologies. Advantages% high containment, one$pot operation and a small "ootprint. The single pot granulation process can compensate "luctuations in raw material speci"ication. 't also oasts a very "ast changeover and easy and sa"e handling o" organic solvents, as well as a high yield and a limited need o" operators. Furthermore, it o""ers a unique solution "or e""ervescent production. Disadvantages: limited throughput, no possi ility "or additional unit operations, and di""icult 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 e uipped with drying technologies. !hus, single pot processing is the production of pharmaceutical granules using a wet granulation process in which dry mixing, li uid addition, wet granulation, drying and si"ing of the granules is done in one machine. #n the remainder of my answers, #$m taking this definition as the starting point. The benefits of this type of processing are:

%y integrating granulating and drying capabilities into a single unit, capital investment in e uipment and good manufacturing practice (&M') floor space is lower than other alternatives. !he number of material handling steps is decreased( conse uently, the total processing time is shorter while maintaining a high yield and keeping production support to a minimum. )t the same time also the number of re uired operators is reduced. *nvironmental variables, such as humidity, are eliminated from the manufacturing process, which may offer advantages for processing moisturesensitive formulations. +e uirements for solvent recovery systems are lower for single-pot processors compared with fluid bed dryers. +eaching a high level of containment is easy by application of the correct measures at in- and outlet valves. ) single pot can be changed over in less than , 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 (-ncology 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 mixergranulators. !he difference in the granulation process between a top- and bottom-driven high shear granulator is not dramatic. %oth types of granulators can produce high uality granulates. !echnically however, with top-driven machines the seals are outside the product which can have &M' advantages. !he main difference between single pot systems lies in the drying technologies they offer. !he basic drying system for all single pot processors is vacuum drying (with heated bowl walls to supply the necessary drying energy). !he advantages of vacuum drying include the low drying temperature and the ease of recovering the granulation li uid, as the vapours are not diluted with air so can easily be recovered by condensation. !his 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.

!he 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. .or water-based products especially when producing large batches - this results in very long drying times at the detriment of the granulate uality. $'ure$ vacuum drying is therefore mainly advised for smaller batches and for solvent-based granulations). /ifferent 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. )lthough 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 0acket of the bowl so is still related to the available contact surface. !his means that gas-stripping technology is still only applicable for smaller, water-based batches. !he technology is also less suitable for solvent-based formulations as the vapours become diluted with noncondensable gasses, which makes 1223 recovery more difficult. .inally, some manufacturers offer microwave drying on single pot processors. !his is the only technology that brings additional energy to the process, and thus will be capable of significantly reducing the drying times. .or water-based formulations, microwave drying technology is certainly the method of choice if a single pot process is considered. )nother advantage of using microwaves during drying is that the temperature of the 0acket of the bowl can now be controlled as it is not re uired to supply the drying energy. !his means that there is a lot more freedom to optimi"e the yield of a process, as the temperature of the 0acket can be set at the correct temperature to avoid the product sticking, without influencing the drying time. !he main drawback of microwave drying is that it is a relatively complex process and re uires both formulators and operators to have a good understanding of the process to ensure that it is developed and executed correctly. .ortunately, all experienced manufacturers of microwave e uipment also offer extensive process support. How have single pot processes improved and advanced during the last decade? !he first single pot processors were developed in the late $42s and the biggest advances in process technology were made in the $52s with, for instance, the introduction of microwaves. #n my opinion, the biggest advances in the field of single pot technology in the last decade have been made in process control, containment and cleanability )s many new applications handle potent oncology medicines, the machines re uire containment. !his doesn$t mean 0ust the addition of high containment valves for loading and discharging6 it also re uires there to be contained sampling when producing validation batches or during production.

7leaning in 'lace is an integral part of a good containment strategy that avoids any contact between the operators and the product. !oday systems are on the market with validatable 7#' systems. What challenges remain to be overcome? )s for many technologies, the implementation of ')! is gradually becoming a given for single pot processes. 8evertheless, 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. !he most advanced systems on the market now have a special ')! probe that can monitor blend homogeneity, granulation li uid distribution, granulation end point and humidity. !he 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? !he regulatory hurdles to change to a single pot process are no different than when changing to any other production method( S9')7 guidelines must be followed to determine what level of change is represented by the switch to a single pot process. .or 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 e uipment (as a single pot processor is a high shear mixer). .or 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. -ne-pot processing is a term that includes any technology that combines different unit operations of a pharmaceutical production process into one machine. #n most cases, however, a onepot processor refers to a high shear mixer:granulator that is also e uipped with drying technologies. !hus, onepot processing is the production of pharmaceutical granules using a wet granulation process in which dry mixing, li uid addition, wet granulation, drying and si"ing of the granules is all performed in one machine. !he benefits of this type of processing are(

%y integrating granulating and drying capabilities into a single unit, capital investment in e uipment and &M' floor space is lower compared with other alternatives. !he number of material handling steps is decreased. 7onse uently, the total processing time is shorter while maintaining a high yield and keeping production

support to a minimum. )t the same time, the number of re uired operators is also reduced. *nvironmental variables, such as humidity, are eliminated from the manufacturing process, which may offer advantages for processing moisturesensitive formulations. +e uirements for solvent recovery systems are lower compared with fluid bed dryers. +eaching a high level of containment is easy by application of the correct measures at in and outlet valves. ) single pot can be changed over in less than , 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. !he concept of a onepot processor in itself already ensures contained processing. %ecause 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. 8o product transfers during the process are re uired, thus drastically reducing the exposure risk. %y applying the correct containment measures to loading and discharge valves, a high level of containment is easily achieved. Process variations -ne-pot processors can be based on top or bottomdriven high shear mixer:granulators. !he difference in the granulation process between a top and bottomdriven high shear granulator is not dramatic. ;ith both types of granulator producing high uality granulates. !echnically, however, with top-driven machines, the seals are outside the product, which can have &M' advantages. !he main difference between onepot systems lies in the drying technologies they offer. !he basic drying system for all onepot processors is vacuum drying (with heated bowl walls to supply the necessary drying energy). !he advantages of vacuum drying include low drying temperature and ease of recovering the granulation li uid, as the vapours are not diluted with air and can easily be recovered by condensation. !his is particularly advantageous when organic solvents are used for granulation6 the emission of organic solvent vapours is very restricted in most countries, but vacuum drying technology allows companies to comply easily with environmental regulations. !he 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. .or water-based products, especially when producing large batches, this results in long drying times at the detriment of the granulate uality. $'ure$ vacuum drying is therefore mainly advised for smaller batches and for solventbased granulations.

/ifferent 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. )lthough 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 0acket of the bowl, so is still related to the available contact surface. !his means that gasstripping technology is still only applicable for smaller, water-based batches. !he technology is also less suitable for solventbased formulations because the vapours become diluted with non-condensable gasses, which makes 1223 recovery more difficult. .inally, some manufacturers offer microwave drying on single pot processors. !his is the only technology that brings additional energy to the process and is, thus, able to significantly reduce drying times. .or water-based formulations, microwave drying technology is the method of choice if a single pot process is considered. )nother advantage of using microwaves during drying is that the temperature of the bowl 0acket can be controlled because it is not re uired to supply the drying energy. !his means that there is a lot more freedom to optimise the yield of a process, as the temperature of the 0acket can be set at the correct temperature to avoid product sticking, without influencing the drying time. !he main drawback of microwave drying is that it is a relatively complex process, and re uires both formulators and operators to have a good understanding of the process to ensure that it is developed and executed correctly. .ortunately, all experienced manufacturers of microwave e uipment also offer extensive process support. Recent advances !he first onepot processors were developed in the late $42s, but the biggest advances in process technology were made in the $52s with, for instance, the introduction of microwaves. #n my opinion, the biggest advances in the field of one-pot technology in the last decade have been made in process control, containment and cleanability. )s many new applications handle potent oncology medicines, the machines re uire containment. !his doesn$t 0ust mean the addition of high containment valves for loading and discharging6 it also re uires there to be contained sampling when producing validation batches or during production. 7#' is an integral part of a good containment strategy that avoids any contact between the operators and the product. !oday, systems are on the market with validatable 7#'. )s for many technologies, the implementation of ')! is gradually becoming a given for onepot processes. 8evertheless, 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.

!he most advanced systems on the market now have a special ')! probe that can monitor blend homogeneity, granulation li uid distribution, granulation endpoint and humidity. !he probe can be cleaned during the process to prevent the product from sticking to the windows. !he regulatory hurdles to change to a one-pot process are no different to changing any other production method( S9')7 guidelines must be followed to determine what level of change is represented by the switch to a onepot process. .or 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 e uipment (a one-pot processor is a high shear mixer). .or 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.