Our continuous pharmaceutical production unit includes all necessary unit operations to convert raw powdered materials to a tablet with the desired coating on it. Continuous feeding, blending, different granulation techniques, transport steps, tableting as well as tablet coating are included in one line with an integrated control concept. The integration of PAT-tools, such as near-infrared (NIR) or Raman spectroscopy facilitates the in-line monitoring of critical quality attributes of intermediates and the final dosage form and enables the integration of closed-loop control algorithms to increase the quality of the desired product and to result in a new generation of pharmaceutical production.
Depending on the characteristics of the starting material and the desired properties of the finished dosage form, the continuous production line allows to choose between direct compression, dry granulation and wet granulation.
The Process - The Next Step in Pharmaceutical Manufacturing
1. Continuous feeding and blending unit
The consistent delivery of raw materials to the unit operations is the basis of each continuous manufacturing process. This step is conducted by the application of powder feeders. The feeding of powders can be problematic, because powders do not behave as liquids regarding their flow behavior. This can be ascribed to cohesion of the powder, possible electrostatic charging, shear sensitivity and changes in bulk densities during processing.
A powder feeder consists of a reservoir for the material that will be fed. Depending on the fill degree of the reservoir, which changes during the process, different normal forces impact the bulk in terms of varying bulk porosities and hence varying bulk densities. The consequence might be a varying output, caused by an unstable filling of the feeding tool of the feeder. The most common type of powder feeding is the screw feeding, which can be carried out by single or co-rotating twin-screw feeders. Other principles, as for example vibratory feeders or scraper feed discs may play a role in the feeding of very small amounts of powder.
Powders can be fed either volumetrically or gravimetrically. Volumetric feeders deliver the material at constant agitation rate of the feeding tool (screw, vibrating chute, etc.), which needs to be calibrated to the corresponding feed-rate beforehand. In these cases the feeder is not capable of displaying the momentary feed-rate of the powder and drifts in the feed-rate cannot be recognized. Furthermore, the feeder cannot react on short-term fluctuations in feed-rate. Consequently, gravimetric feeding of powders is state of the art in the pharmaceutical industry. Gravimetric feeders are based on volumetric feeders, which are placed on and electronically coupled to a dynamic balance, also called a loading cell.
The loading cell measures the weight loss during a feeding process in high frequency and consistently sets the motor speed by integrated and mostly self-optimizing controllers, to meet the desired feed-rate. Thereby, a momentary feed-rate can be monitored and recorded and inaccuracies of the feeder can be levelled off. From the view of Quality by Design and process control, the knowledge of the momentary feed-rate is essential, as the feeding displays the introduction of raw material to the process. Disturbances can directly be measured and the process can react to them for instance via integrated feed-forward loops.
In a continuous process, the powder reservoir of a feeder will be empty at some time point and has to be refilled, frequently. During this refill phase, the feeder is shifted to volumetric feeding mode, because the gain in powder weight would be recognized by the balance and all controls of the feeder would be confused, which results in huge feeder errors. Consequently, during this refill-phase the powder feeder is blind to deviations from the set feed-rate and cannot react on those. It is obvious that an overfill of the screw flights during the refill phase, caused by a fast densification of the powder inside the reservoir, led to a periodic overfeeding during all refill phases. It is suggested to find an adequate ratio between a gentle refill of the reservoir and the refill time, to keep the refill time and the deviations as small as possible [Quelle: W.E. Engisch, F.J. Muzzio, Feedrate deviations caused by hopper refill of loss-in-weight feeders, Powder Technol., 283 (2015) 389-400].
The GZD feeder by Gericke AG represents a state of the art device for volumetric and gravimetric screw feeding of powders and granules. Equipped with a high-precision scale and a non-linear, data driven control system, the feeder is able to achieve outstanding and consistent results for feeding accura-cies even for difficult products, detecting and compensating external influences to the process. For each raw component a separate feeding unit is required, to dispense the com-pound into the downstream blending process.
Both for volumetric and gravimetric feeding, the operational range of the feeder can be adjusted by selecting different hopper sizes as well as screw configurations as listed in the following. By default, each feeder is shipped with one hopper and one pair of screws.
The screw design is determined by multiple parameters and directly affects the feed-ing process and accuracy. More specifically, the parameters are:
- Screw pitch
- Flight layout (self-cleaning, full blade, centerless)
- Number of screw flights
Based on the raw material assessment, the optimal feeding screws for the compound at a given feed rate have to be selected from the available design. Optionally, custom screw designs can be engineered and manufactured.
The content uniformity (CU) is one major CQA to achieve within a finalized dosage form. Feeding is a crucial unit operation to achieve CU, but can be problematic, as explained before. In truly continuous processes every excipient and API usually is delivered by its particular feeder, which also gets refilled following a scheme, depending on the feed-rate of the ingredient. This complicates CU issues even more. Normal feed-rate deviations and deviations caused by refill phases of the feeder will arise constantly. Continuous blenders can be applied to dampen feeder fluctuations before a particular unit operation. In contrast to batch blending, during continuous blending only small amounts of material are blended at the same time, the blending time is short and the footprint of the machine is smaller. Depending on the overall throughput of the continuous process and the design of the blender there are a few grams up to a few kilograms within a process, at once. Continuous mixing relies on axial mixing and thus broad residence time distributions, to dampen feeder fluctuations and to reach the desired CU.
The continuous blender is a Gericke GCM450P, state of the art paddle blender for gentle mixing of powders and granules. With its process chamber length of 450 mm it allows for short residence times and throughputs between 5kg/h up to >100kg/h. The blending process is adjusted by varying the energy input based on the paddle speed and product hold-up based on the weir position.
The stainless steel construction provides a hygienic design for pharmaceutical applications. The blender consists of the drive body, the process chamber and the weir and transition element at the end. The entire is blender is mounted to the base plate by a fix-ture to the drive body, with an optional integration of a blender scale. In our demonstration line in the Technology Center in Ennigerloh, Germany, up to four ingredients can be dosed and blended at the first feeding/blending station. A maximum number of six feeders can in general be controlled at one feeding/blending station.
2. Dry / Wet granulation
A twin-screw granulator is the core of our wet-granulation based continuous manufacturing solution and a truly continuous process, by nature. The machine is named Bohle Continuous Granulator (BCG 25) and comes along in Pharma-complient design.
A twin-screw granulator is defined by the screw diameter and the length to diameter ratio of the screws. The demonstration line in the Technology Center in Ennigerloh, Germany features a twin-screw granulator with a screw diameter of 25 mm and a length-to-diameter ratio of 20. Furthermore, the BCG consists of of a split barrel, which can be opened up for a fast changeover of the screw configuration and fastest cleaning accessibility.
The BCG 25 is divided into five zones of equal length, from which the last three zones can be heated and cooled independently from each other. Heating and cooling is carried out on the upper and the lower part of the split barrel with specially designed and innovative tempering zones, ensuring the most effective temperature control in twin-screw granulation machines on the market. Each zone offers the possibility to insert different ports on top of it. Thereby, powder feeding, differently executed liquid feeding, venting and the application of PAT-tools become feasible. Our solution for liquid-feeding consist of a special design to guarantee most accurate and precise feeding, without a blockage of the nozzle, even at lowest liquid feed-rates. The screw is not a predefined parameter in twin-screw granulation processes. Virtually, an infinite number of different screw configurations is possible by combining different types of elements. Conveying elements are used to convey the material through the barrel with minimal input of shear energy. The pitch of the elements can be varied. With increasing pitch of the elements, the conveyed mass per revolution decreases. Kneading elements are thin discs or blocks with variable length and can be combined to different kneading zones. The imparted shear energy increases and the conveying capacity decreases with an increasing advanced angle of the subsequently arranged kneading discs. An intermediate between these two extremes is represented by distributive flow elements, which feature conveying capacity as well as shear energy. Through combination of different elements, granule characteristics can be influenced and the necessary properties for the subsequent unit operations can be adjusted. The fill-level of the BCG 25 depends on the feed-rates of the material, the screw speed of the extruder and the geometry and thus the free volume of the extruder screws.
However, a twin-screw granulator displays an ideal tool to perform continuous granulation, because it combines several processes. Conveying, mixing, wetting and shearing take place in one machine in exceptionally short time.
A process factor that is influenced by a lot of parameters and can only be adjusted qualitatively is the residence time distribution (RTD), which describes the probability of material to stay inside the granulator during a steady-state process. It is essential to know the RTD and the influencing factors on RTD to understand a continuous process and to control it properly.
The BCG 25 is also an efficient blender. The flow in such a granulator is similar to that of a continuous paddle blender mixer. Different kneading and mixing elements can prolong residence times and introduce axial mixing into the process. Consequently, even mixtures which might not be mixed sufficiently, after a continuous blender, can be processed, further, because the BCG can dampen the fluctuations of powder feeders even more.
Semi-continuous drying (BCD 25) for pharmaceutical apllications
After twin-screw granulation in the BCG, the granules have to be dried for subsequent processes. A transfer to the drying system by vacuum is necessary, but considerations regarding granule strength have to be arranged to prevent a destruction or desagglomeration of the granules. To prevent secondary agglomeration of the wet granules and to handle huge throughputs, fluid bed techniques for drying are the only reasonable drying method.
One fundamental requirement to operate this process is a reproducible RTD to ensure a constant drying and residual moisture in the dried granules.
Dry Granulation BRC for pharmaceutical applications
The most common way and the only possibility to conduct dry granulation continuously is roll-compaction / dry-granulation, which is a continuous process, by nature. Within our demonstration line in our Technology Center in Ennigerloh, Germany the Bohle Roll Compactor (BRC 25) is located which on the one hand can serve as research and development machine and on the other hand fits perfectly to a continuous manufacturing line with throughputs of up to 50 kg/h. During roll compaction, powder is transported by a combination of a feeding- and one or more temping-screws constantly to the nip region of two counter rotating rolls. The powder experiences a densification as it passes the rolls, resulting in the generation of ribbons, which are flat, band-shaped products. To result in strong ribbons, the usage of a dry binder within the powder mixture is essential, which often are derivatives of cellulose, starch or povidone. After the compaction process, the dry granulation process takes place by milling the ribbons to granules. After granulation the granules are transported to a second feeding/blending-step to be prepared for subsequent tableting.
The possibilities to influence the granulation by different critical process parameters (CPP) are manifold, starting with the roll compaction process, in which feed-rate, roll surface, roll speed, specific compaction force, gap width and the roll sealing system can be adjusted. Roll types, such as fluted rolls, smooth rools, knurled rolls are available as a standard, but specific designs for special purposes have already been implemented in production processes.
By the machines control system, the gap between the rolls and the specific compaction force have to be maintained on a constant level to ensure constant ribbon porosity and thus constant compactibility, compressibility and size distribution of the granules. Through intensive collaboration work, we can present the most effective control system for the specific compaction force and the gap width of the rolls. Thereby the BRC manages to maintain both quantities in very narrow limits, to ensure a proper state of control during continuous manufacturing mode.
The milling process can be influenced by the type of mill. L.B. Bohle offers as standard a conical mill, which is also available as standalone machine, which is the Bohle Turbo Sieve (BTS). As alternative and to have another factor to influence the granule size distribution, the Bohle Rotation Sieve (BRS) can also be implemented. This kind of sieve offers the possibility of rotation and oszillation, to adapt the mill type to the process and to the formulation.
A quick changeover of the two sieve systems and an automated recognition of the milling system by the BRC is the advantage, which is needed for a fast changeover of products or in R&D work.
Other important factors during the milling process are the mill speed, the screen type and size of the applied sieve. The major advantage of a roll-compaction / dry granulation process is the absence of moisture and thus of a drying step. Thereby, the processing time from powder to finished granule is short and from an economic point of view saves energy and CO2-emission.
The design is completed by the wash-in-place (WIP) implementation, which is a standard part of the BRC. Thereby, a complete wetting of the residual powder within the BRC can take place, operator protection from dust is ensured and the cleaning time of the machine becomes even faster.
3. Continuous feeding and blending unit
The second feeding blending station is directly located on top of the tablet press. The principle is equal to this of the first feeding/blending station. Using continuous direct compression, this station is the first unit operation, as all ingredients a continuously dispensed, here. In a larger framework with a granulation process, upstream of the second feeding/blending station, this station serves to add extragranular excipients and to result in the final tableting mixture. Typically, disintegrants or glidants are added at this point of the process. To prevent an overmixing of magnesium stearate within the tableting mixture, which is the most common used glidant, the addition point of this ecipient is at the last part of the continuous paddle blender.
4. Tablet press
Within our demonstration line we teamed up with the Korsch AG as the provider for the tableting machine, which is the world-wide leading expert in tablet compression technology. The XL 200 is a robust, high-speed rotary tablet press (single-sided) with state of the art technology, which is ideal for scale-up, clinical manufacturing, and high-speed production.
The feed frame is supplied by the upstream process (2nd Feeding/blending unit) and features a level monitoring in the product supply. When passing by the feed frame, the die is filled with the powder or granules, using a volumetric dosing mechanism. With the die filled, the upper punch is lowered before entering the pre-compression zone. After the pre-compression, the main compression of the tablet core takes place with equal or higher compression force. If necessary, a hold bar can be installed to keep up the compression force between pre-compression and main compression zone. After the main compression, the produced tablet is transported to the ejection zone. Using a feed-forward control, single tablets can be rejected into the reject outlet, e.g. if the measured compression force was not within the defined limits. Furthermore, samples can be taken from the process and released through the sample outlet into an automatic tablet checker. Finally, all tablets within specification a released into the next processing step through the good outlet.
The design concept of the XL 200, including the rear multi-function cabinet with all major press components, and open compression zone, offers superior access for operation, cleaning, changeover, and maintenance. The compression zone of the XL 200 features minimal components and smooth surfaces to streamline the changeover process. The XL 200 is built to operate at high-speeds, with maximum efficiency and reliability.
Although achieving up to 120 rpm at 40 kN precompression force, respectively 80 kN main compression force, the XL200 features a quiet operation, due to the floating carrier plate of the entire compression unit. The carrier plate is carried by an air suspension system, decoupling the compression column and rotor as sources of vibrations from the machine frame. This design not only allows quiet operation even at high compression speeds, but also improves the process by cancelling out vibrations in the feed pipe, which might otherwise cause segregation of the material stream in.
Using exchangeable turret capability, the XL 200 permits the production of a high variation of tablet sizes on a single machine.
Depending on the engaged punch size, compression force and chosen product, the XL 200 can carry out a tablet output up to 230000 tablets /h or a maximal tablet diameter of 25mm.
For easy cleaning, the XL200 can be equipped with a Wash-in-Place (WIP) capability for the entire compression zone. After production, a full wetting of all product contact parts can be performed, using a recipe controlled WIP sequence for the integrated cleaning nozzles. This is especially important for OEB 3 and higher.
5. ROB 50
The ROB 50 is a robotic system for handling of tablet containers, to close the gap between the tablet press and film coating process. The handling robot ROB 50 is interfaced with both the tablet press and the downstream coating process, implementing an autonomous transfer system with integrated container storage and inventory system.
During operation, a status signal from the tablet press is sent, if one of the two containers after the deduster has been completed with a new filling of tablets for the coater. This signal triggers the ROB 50 to pick up the full container, move it into the container storage and replace it by an empty container. On the one hand, the container storage serves as a buffer between tablet compression and coating, but on the other hand is used to allow the recently compressed tablets in the containers to cure, according to the product specific time for elastic recovery. Therefore, the configuration of the container storage, especially in terms of capacity, is built customer and product specific.
On the other side of the production chain, the coater can request a container with tablet cores, to be fed into the coater for a new coating cycle. Based on the data in the inventory system, the ROB 50 picks the container next in line, moves it to the coater and discharges the tablet cores into the coating pan. Of course, the integrated inventory system ensures that the tablet cores are kept in the container storage at minimum for the required tablet core relaxation time.
The KOCO 25 is designed as a semi-continuous coater, featuring a reliable throughput while ensuring a constant residence time for all cores. The process machine is built on the industry proven, patented Bohle design for drum coaters. That is, the coating pan is elongated in comparison to the diameter, with two helical mixing spirals, which ensure a homogeneous distribution and mixing of the tablets throughout the spray zone. Additionally, the process air both enters and exits the process chamber through the tablet bed, which in comparison to a typical, diagonal air flow reduces spray drying to a minimum.
The spray arm features an automatic adjustment of the spray angle and distance, carrying a total of six, two-substance spray nozzles. Furthermore, the spray system includes recirculation and single supply of the spray nozzles, to ensure a homogeneous and reliable application of the coating suspension.
In contrast to common batch coaters, the KOCO 25 uses a feeding of tablet cores through a product inlet port on top of the machine, leading to an opening in the rear of the coating pan. This port is normally closed and the product valve is only opened to fill the drum for a new coating cycle. The discharging of the coated tablets is through a corresponding port at the front of the coater. The process control is designed to operate in a cyclic manner, to repetitively execute the defined recipe, each execution further denoted as cycle. An integrated Raman probe aids the operator to detect the end-point of the coating process, after a suitable chemometric model has been built.
Depending on the function of the coating (e.g. cosmetic, taste masking, active coating, modified release) the size or the number of the coaters can be adapted to maintain the aimed throughput of the continuous manufacturing line.
- Small footprint
- Production capacity: ~5-25 kg/h
- Operational volume 7 to 20 liters
- 6 spray guns
- Spray rates of 120 g/min and above
- Bohle specific helical baffle design
- Separate feeding & discharge for fast changeover
- Air flow 600+ Nm³/h
The continuous production module features a full integration of PAT (process analytical technology) tools using Siemens Simatic SIPAT as the PAT data management system, whereas the integration of other systems such as Optimals synTQ is also possible, if desired by the customer. PAT is the core and the heart of a truly continuous process. It has the potential to replace traditional quality control of intermediates and the finished dosage form, as it consistently monitores the critical quality attributes (CQA) of them. Without PAT it is virtually impossible to control a continuous process with respect to desired product properties and the overall product quality. Because one major requirement for every single product is to detect and validate a suitable design space. A design space is considered as an area of each critical process parameter (CPP) and raw material attributes, in which the intermediates and especially the finished product conform to the defined critical quality attributes. To really control a continuously running system and to maintain a stable process, the information from PAT-sensors must not only be read and monitored but connected to the design space, in such a way to enable a reaction of the central control system to disturbances of the process or to trends leading out of the design space.
The main task of a control system is to modify the variables, which are susceptible to manipulations (i.e. CPPs) and to maintain steady-state conditions. Myerson et al. [A.S. Myerson, M. Krumme, M. Nasr, H. Thomas, R.D. Braatz, Control systems engineering in continuous pharmaceutical manufacturing, May 20-21, 2014 Continuous Manufacturing Symposium, J. Pharm. Sci., 104 (2015) 832-839] avoided the phrase steady state and called it quasi steady state, in which the CPPs can be varied according to the design space. They declare that the aim should rather be to continuously conform to the specifications of the CQAs than to maintain a steady state of all CPPs.
In the continuous manufacturing line at L.B. Bohle we use different types of PAT-sensors to follow the product through the manufacturing process and to ensure homogenous product quality through interventions of the central control system. However, the system is not limited to the subsequently mentioned sensors and an integration of further types is feasible, if desired.
Near-infrared spectroscopy (NIR) is applied for different purposes in our Technology Center in Ennigerloh, Germany. Within the first and the second feeding/blending unit it is applied to measure the blend uniformity or the content of the applied active pharmaceutical ingredient (API). Thus, after each FBU a PAT checkpoint with a probe, followed by a product diverter is installed. The probe is connected to a corresponding spectrometer, recording spectra according to the configured sampling rate. The spectrum is transferred to the SIPAT system and analyzed by the preferred calculation engine, using the PAT model created in the development phase. The result of this model-based analysis can be a qualitative or quantitative assessment of the blend quality, API content etc. If the analysis indicated that the product is out of specification, the control system triggers the diverter downstream the product flow to swap to the rejection position.
Another application of the NIR is the drying process after continuous twin-screw granulation. Within each chamber of the semi-continuous fluid-bed dryer, an NIR-probe is implemented, which is able to measure the moisture of the product. It thereby monitores the drying process and provides an endpoint detection of the drying process. This is an important function as the initial moisture of the wet granules or the amount of material in each chamber might deviate. Thus, consistent residual moisture of the dried granules is ensured. Without a proper monitoring and in-line control of the granule moisture, inconsistent results throughout the sub-batches were a consequence.
In addition to NIR for analyzing the blend homogeneity and the granule moisture, L.B. Bohle with the cooperation of the University of Düsseldorf did plenty of research regarding the use of Raman spectroscopy for monitoring and controlling coating processes in-line. Depending on the Raman activity of either the tablet formulation or the coating suspension, this technology allows to identify the coating progress and detect the endpoint based on a chemometric model.
The KOCO 25 (semi-continuous tablet coater) is equipped with a Kaiser RX4 Raman PhAT-probe. By the non-destructive measurement, the required coating-thickness can be detected and the signal to finish the coating process is sent to the control system, which facilitates the discharging of the KOCO and the charging with a new sub-batch, to start the process-cycle again.