Griet Van Vaerenbergh

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. 

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. 

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. 

 is Product Manager Single Pot Processing at GEA Pharma Systems – Collette. 

This article is part of a special feature on granulation that was published in the March issue of PTE Digital, available at 

Articles

One-pot processing is a term that includes any technology that combines different unit operations of a pharmaceutical production process into one machine.

One-Pot Processing And The Benefits For Granulation

The requirements of a granule drying process haven't really changed much in recent years: pharmaceutical companies still need a process/technology that is capable of drying the produced granules as fast as possible, without affecting critical quality attributes (CQAs), such as particle size and homogeneity. However, as with all other pharmaceutical processes, the pharma industry has started to focus on quality by design (QbD) for the development of granule drying processes. As such, companies are now working on controlling and analysing CQAs inline and during the process, as well as understanding the process better and correcting it when necessary, rather than analysing the product afterwards without a thorough understanding of what might have gone wrong during the process in case of an outofspecification result. 

Two major breakthroughs in granule drying technologies have taken place in recent years: the development of better and more robust and integrated PAT tools and probes, with the ability to clean and calibrate without interrupting the process, and the introduction of continuous processing for granulation and drying. The use of PAT tools for inline/inprocess measurement of CQAs has helped the pharma industry obtain a better understanding of processes, which makes it possible to implement QbD in the development of new products, as well as to improve current processes. This helps to improve production efficiency, product quality and safety. 

However, with current batch drying technologies, it is often not possible to correct a detected out-of-specification situation during the process, which is why the introduction of continuous granulation and drying technologies is so important. A continuous system is ideally suited for the implementation of online PAT measurements because it is very easy to detect a deviation from steady state and to modify the process parameters 

 a feedback (or even feed forward) loop to prevent the product from becoming out-of-specification. This development will lead to better process control, high production efficiency, less wasted product, and better product quality and safety. 

Drawbacks of existing systems and solutions

One of the main drawbacks of current drying systems is that they are all batch systems. Even with the implementation of on-line measurement tools, batch processes are more difficult to understand and control because they are in a continuous state of change. As mentioned above, when an outofspecification result is detected in batch systems, it is often not possible to correct it by changing process parameters and a complete batch is wasted. 

Continuous systems can overcome this problem. As a continuous system reaches a steady state, it is much easier to understand and control. An advanced control system continuously monitors the process and when it detects a trend to deviate from steady state, it will automatically take action by changing process parameters to avoid out-of-spec results. In newly developed continuous systems, steady state is reached very fast and there is always only a small amount of product in process; in the unlikely event that out-of-spec product is produced, only a small amount needs to be discarded. 

Because of the advantages, we will see a move from batch systems to continuous systems, and a widespread implementation of online measurement tools and advanced control systems, such as those already seen in the chemical industry, only on a smaller scale. I also believe that continuous systems will be more flexible; not continuous systems producing only a single product for years, but systems that can produce several products in campaigns of varying length. 

Additionally, given the fact that a tablet press is already a continuous process, we will see the implementation of truly continuous production systems, going from powders to tablets without products in quarantine waiting to be released after drying and before tabletting. With advanced control systems containing feed forward and feedback loops, the online measurements of CQAs will be sufficient for realtime release.

The requirements of a granule drying process haven't really changed much in recent years.

Drying: moving from batch to continuous processes

During recent years, concern regarding the cleanability of pharmaceutical processing equipment and operator exposure to active pharmaceutical ingredients (APIs) has been steadily growing, driven mainly by the increasingly strict regulations regarding operator safety and the occurrence of more potent active compounds. As a result, most process equipment is now equipped with integrated clean-in-place (CIP) systems. This article examines the CIP system of a one-pot processor and describes how effective it is at removing two different types of drug compound - water-soluble theophylline and water-insoluble mebendazole.	

Materials. The theophylline batch formulation comprised 65% lactose 200 mesh (DMV International, The Netherlands), 5% PVP K25 (BASF, Germany) and 30% theophylline (Medeva Pharma, Belgium). Two per cent P3-cosa CIP-95 detergent (Ecolab, Belgium) was used to wash the theophylline. P3-cosa CIP-95 is a detergent based on alkali and complexing agents, and a 1% solution has a pH of 12.3–12.7 at 20 Â°C in deionized water. It does not contain tension-active ingredients. The one-pot processor used was the UltimaPro 75 (Collette NV, Belgium).				

Batch production. All raw materials were loaded into the system's bowl using its vacuum loading system and then dry mixed. Water (1.8 kg) was added using a pressure vessel to granulate the material, and the batch was dried using vacuum, microwaves and the swinging bowl. A dust-free method was used to discharge the batch into a drum. Total production time was 50 min, during which the processor was kept closed to simulate actual conditions when working with potent compounds.	

Cleaning cycle. The cleaning cycle began by prewashing the product feed tube, the gas-assisted vacuum system (Transflo), the liquid addition system and the bowl with water (35 L, 40 ÂºC). 	

After discharging the prewash water, the product filter was cleaned using hot water and detergent. The swinging bowl was filled with detergent, and both the bowl and lid were cleaned whilst the mixer and chopper operated at high speed. The solution was discharged and the discharge valve was cleaned with hot water and detergent. The total volume of hot water (60 Â°C) used was 80 L.

Cold water (60 L, 20 Â°C) was used to remove any residual detergent followed by a final rinse with demineralized water (50 L, 20 Â°C). The supply lines for the cleaning media were blown dry with purified process air. Finally, the machine was dried using vacuum, gas-assisted vacuum and the heated jacket. The total cleaning cycle took approximately 90 min, 30 min of which were spent drying and preparing the machine for the next batch. 	

Four theophylline batches were produced to evaluate the cleaning phase's reproducibility. The system was cleaned immediately after each production run with the exception of one batch for which cleaning was delayed by 24 h.	

Sampling. Following each batch production, samples were taken from six areas of the processor - the product filter, impeller, chopper, bowl and lid, gas-assisted vacuum system and discharge valve. These regions were selected because it is critical that they are cleaned between runs. Both the stainless steel surfaces of the areas and their surrounding seals were evaluated (Table I). Samples were taken using the swab method, wetting a swab tissue with 2 mL of ultra-pure water. Swab surfaces were predetermined and their exact size was known.	

Product filter. Although the total surface in contact with the product is 1524.5 cm2, the sample from the product filter was taken from a surface area of 100 cm2 from the lowest part of the filter, that is, the area in closest contact with the product (particularly during swinging). 	

Impeller. The wingnut was located centrally at the bottom of the impeller and, because of its location, was included in the study. The impeller blade was one of the largest parts in direct contact with the product. To ascertain exactly how much product remained on the impeller blades (front and back surfaces), it was completely swabbed. 	

The lipseal of the impeller shaft was deemed to be a critical region of the processor because it is not flush with the lid and no spray balls are available in the lid for this size of machine. This area was included in the study to see whether agitating the water with the mixer was sufficient to clean this part.	

Chopper and bowl. The chopper knife and a 100 cm2 surface area of the bowl were deemed critical because these parts were in direct contact with the product. Any remaining residue would, therefore, contaminate subsequent batches.	

Discharge valve. Although the contact time between the product and the discharge valve was short, there is considerable risk that residues remaining in this area would contaminate the next batch.	

Despite the design of the processor preventing direct contact between the bowl seal and the product, the seal was included as a critical area because water could infiltrate the small gap between the bowl and lid rims. Finally, the Transflo opening was included to assess the possibility of water seeping through the filter and being trapped there. After the cleaning cycle, samples of the final rinse water were collected to ensure elimination of the detergent.	

Swab sample analysis. After transfer of the swab in a borosilicate tube (Corning Glass Works, USA), 5 mL of distilled water was added. The tube was vortex-mixed for 10 s, homogenized in an ultrasonic bath for 1 min and 250 mL of the solution was injected into a column.	

The chromatographic system consisted of an isocratic pump (L-7110), a variable wavelength UV detector (L-7400) and a PC-interface (D-7000) (complete system manufactured by Merck-Hitachi, Germany), while the integration of the peak area was performed using the HPLC system manager V3.0 (Merck-Hitachi, Germany). The analytical column (25034 mm i.d.) was packed with 5 Âµm RP-C18 particles (Licrosphere; Merck, Germany). Samples were manually injected using a syringe-loaded injector (Valco six-channel injector; Valco Instruments, USA) and a loop of 250 ÂµL. The mobile phase, consisting of 50% (v/v) MeOH and 50% (v/v) distilled water, was degassed before use and had a flow rate of 1.0 mL/min. 	

The UV detector monitored the theophylline concentration at 280 nm. All experiments were run at ambient temperature. Stock solutions of theophylline at a concentration of 100 mg/mL were prepared in distilled water, stored at 8 Â°C in stoppered flasks and used to prepare a set of six calibration standards; concentrations varied (0.01–100 Âµg/mL). The method was linear across the concentration range (R250.9991). The within-day variability (n55) was 0.28% whereas the inter-day variability compared with the above-mentioned concentration range was determined at 0.33%. The detection limit was determined at 2.1 ng/mL, thus the quantification threshold was 14.7 ng/swab.	

Analysis of the rinse samples. To determine detergent residues in the final rinse water, a conductivity measurement was made using the LF 325 conductivity meter (WTW GmbH & Co. KG, Germany). The samples of the final rinse water were compared with blank samples of the demineralized water used for rinsing and samples of a 1:1000 dilution of detergent solution.	

Acceptance criteria. Two criteria were calculated to ensure the cleaning cycle was validated - the 10 ppm criterion and the absolute mass criterion. The acceptable quantity of a product per swab can be calculated as follows:	

Based on formulation density and the bowl's requirement to be at least one-third full to be impacted by the chopper during granulation, the smallest theophylline batch was 12 kg. Initial trials on the swab determined that the theophylline recovery was between 95–100%. Nevertheless, the Factor 2 for swab yield was maintained in the formula for calculating the acceptance criteria, to account for any operator influence.	

For absolute mass, the acceptance limit for an active substance is defined as 1 Âµg/cm2, which was used as the acceptance criterion in this study. The acceptance criterion for residual detergent traces is that the conductivity of the final rinsing water should be lower than the conductivity of a 1:1000 dilution of the detergent solution.	

Materials. The raw materials for the mebendazole batches were provided in a premixed blend by Janssen Pharmaceutica (Beerse, Belgium). Three detergents (all Ecolab) were used for the cleaning cycle:				

P3-cosa CIP-92, an alkaline detergent containing surfactants. A 1% solution in 20 Â°C in deionized water has a pH of 11.5–12.5. A 2% concentration solution was used in this study

P3-cosa PUR-84, a liquid additive for the alkaline detergent based on complexing agents, surfactants and sequestrants; used together with the alkaline detergent at a concentration of 0.75%

P3-cosa CIP-72, an acid detergent containing different organic acids, used in a concentration of 2% for the neutralization of the alkaline detergent and the removal of the additive.

Batch production. All raw materials were loaded into the bowl using the vacuum loading system and dry mixed. Water (12 kg) was added using a pressure vessel for granulation of the material. The batch was dried using vacuum, microwaves and the swinging bowl before being discharged into a drum using a dust-free method. Total production time was 125 min. During production, the processor was closed to simulate actual conditions when working with potent compounds.	

Cleaning cycle. The mebendazole cleaning cycle differed from the theophylline cleaning cycle in the following ways:	

hot water (175 L, 60 Â°C) was used in the prewash

for the first cleaning cycle, an alkaline detergent combined with an additive was used

the cold water rinse was replaced by cleaning with acid detergent to neutralize the alkaline detergent

after rinsing with acid detergent, a "once-through" cycle of the Transflo, the product filter, bowl, lid and discharge valve with hot water was performed to remove traces of acid detergent.

The total volume of hot water (60 Â°C) used for all steps in the cleaning cycle was 175 L. The final steps of the cleaning cycle (including 50 L demineralized water) were identical to those of the cleaning cycle for theophylline. The total cleaning cycle took approximately 100 min, 30 min of which were spent drying and preparing the machine for the next batch.	

To evaluate the reproducibility of the cleaning cycle, three production runs were performed, followed by cleaning. The equipment was cleaned 24 h after the run.	

Sampling. Samples were taken from the same areas as those taken for the theophylline runs, that is, product filter, impeller, chopper, bowl and lid, gas-assisted vacuum system and discharge valve. Again, both stainless steel surfaces and seals were evaluated (Table II). Sampling was done using the swab method, although the swab tissue was wetted with analytical grade concentrated methanol. The swab surfaces were predetermined and the exact size known.	

The sample area of the discharge valve was the piston rather than the cover as used for the theophylline runs to get a better overview of the cleanability of the valve's parts. Also, for the mebendazole study, samples were taken from the final rinse water to determine detergent residuals.	

Swab sample analysis. The swab was dried in the sample tube, after which 20 mL of a formic acid/dimethylformamide mixture (1:9, v/v) was added. The tube was shaken for 60 min and filtered through an Acrodisc 0.45 mm filter (Pall Corporation, USA) and 10 mL of the filtrate was injected into the column. 	

This article describes the use of a one-pot processor for the cleaning and cleaning validation of two drug compounds - water-soluble theophylline and water-insoluble mebendazole. Both substances were produced using wet granulation and microwave drying, after which the processor was cleaned using its clean-in-place (CIP) system. Swab samples were taken from areas considered critical during processing and analysed for remains of active ingredient. It was concluded from the results that the processor's CIP system is capable of removing both moieties to a level well within accepted regulations.