Review the process to make sure that proper analytical instrument is available. Personnel should be trained to perform the test. Reliability of the test should be checked. At last assay procedure should be reviewed before transfer. The design and construction of the pharmaceutical pilot plant for tablet development should incorporate features necessary to facilitate maintenance and cleanliness. If possible, it should be located on the ground floor to expedite the delivery and shipment of supplies. Extraneous and microbiological contamination must be guarded against by incorporating the following features in the pilot plant design: Fluorescent lighting fixtures should be the ceiling flush type.
The various operating areas should have floor drains to simplify cleaning. The area should be air-conditioned and humidity controlled. High -density concrete floors should be installed. The walls in the processing and packaging areas should be enamel cement finish on concrete. Equipment in the pharmaceutical pilot plant should be similar to that used by production division- manufacture of tablets.
If a system is used to transfer materials for more than one product steps must be taken to prevent cross contamination. Any material handling system must deliver the accurate amount of the ingredient to the destination. The type of system selected also depends on the characteristics of the materials. More sophisticated methods of handling materials such as vacuum loading systems, metering pumps, screw feed system. Inadequate blending at this stage could result in discrete portion of the batch being either high or low in potency.
Steps should also be taken to ensure that all the ingredients are free of lumps and agglomerates. The equipment used for blending are: V- blender Double cone blender Ribbon blender Slant cone blender Bin blender Orbiting screw blenders vertical and horizontal high intensity mixers. To impart good flow properties to the material, 2.
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To increase the apparent density of the powders, 3. To change the particle size distribution, 4. Uniform dispersion of active ingredient. Wet granulation can also be prepared using tumble blenders equipped with high- speed chopper blades. Fluidized Bed Granulations : 1. Process Inlet Air Temperature 2. Atomization Air Pressure 3. Air Volume 4. Liquid Spray Rate 5. Nozzle Position and Number of Spray Heads 6. Product and Exhaust Air Temperature 7. Cleaning Frequency 9. Bowl Capacity 4 Binders: Used in tablet formulations to make powders more compressible and to produce tablets that are more resistant to breakage during handling.
In some instances the binding agent imparts viscosity to the granulating solution so that transfer of fluid becomes difficult. This problem can be overcome by adding some or all binding agents in the dry powder prior to granulation. Some granulation, when prepared in production sized equipment, take on a dough- like consistency and may have to be subdivided to a more granular and porous mass to facilitate drying. This can be accomplished by passing the wet mass through an oscillating type granulator with a suitably large screen or a hammer mill with either a suitably large screen or no screen at all.
The important factor to consider as part of scale-up of an oven drying operation are airflow, air temperature, and the depth of the granulation on the trays. If the granulation bed is too deep or too dense, the drying process will be inefficient, and if soluble dyes are involved, migration of the dye to the surface of the granules. Drying times at specified temperatures and airflow rates must be established for each product, and for each particular oven load.
Fluidized bed dryers are an attractive alternative to the circulating hot air ovens. The important factor considered as part of scale up fluidized bed dryer are optimum loads, rate of airflow, inlet air temperature and humidity. Tray Dryer-- Parameters to be considered for scale up are : 1. Air flow 2. Air temperature 3. Depth of the granulation on the trays 4. Monitoring of the drying process by the use of moisture and temperature probes 5. Drying times at specified temperatures and air flow rates for each product Fluidized Bed Dryer : Parameters to be considered for scale up are : 1.
Air Flow Rate 3. Inlet Air Temperature 4. Humidity of the Incoming Air 6 Reduction of Particle size Compression factors that may be affected by the particle size distribution are flowability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness, and tablet color uniformity.
Particle size reduction of the dried granulation of production size batches can be carried out by passing all the material through an oscillating granulator, a hammer mill, a mechanical sieving device, or in some cases, a screening device. As part of the scale-up of a milling or sieving operation, the lubricants and glidants, which in the laboratory are usually added directly to the final blend, are usually added to the dried granulation during the sizing operation. This is done because some of these additives, especially magnesium stearate, tend to agglomerate when added in large quantities to the granulation in a blender.
In any blending operation, both segregation and mixing occur simultaneously are a function of particle size, shape, hardness, and density, and of the dynamics of the mixing action. Particle abrasion is more likely to occur when high-shear mixers with spiral screws or blades are used. When a low dose active ingredient is to be blended it may be sandwiched between two portions of directly compressible excipients to avoid loss to the surface of the blender. In scale up of blending , following parameters should be considered - 1. Blender loads , 2. Blender size , 3.
Mixing speeds , 4. Mixing times , 5. Bulk density of the raw material must be considered in selecting blender and in determining optimum blender load 6. This is done on a tablet press designed for slugging, which operates at pressures of about 15 tons, compared with a normal tablet press, which operates at pressure of 4 tons or less. Dry Compaction Granulation by dry compaction can also be achieved by passing powders between two rollers that compact the material at pressure of up to 10 tons per linear inch.
Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression. One of the best examples of this process is the densification of aluminum hydroxide.
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Pilot plant personnel should determine whether the final drug blend or the active ingredient could be more efficiently processed in this manner than by conventional processing in order to produce a granulation with the required tabletting or encapsulation properties. Compression The ultimate test of a tablet formulation and granulation process is whether the granulation can be compressed on a high-speed tablet press.
During compression, the tablet press performs the following functions: 1. Filling of empty die cavity with granulation. Precompression of granulation optional. Compression of granules. Ejection of the tablet from the die cavity and take-off of compressed tablet. When evaluating the compression characteristics of a particular formulation, prolonged trial runs at press speeds equal to that to be used in normal production should be tried. Only then are potential problems such as sticking to the punch surface, tablet hardness, capping, and weight variation detected.
High-speed tablet compression depends on the ability of the press to interact with granulation. Following are the parameters to be considered while choosing speed of press. Granulation feed rate. Delivery system should not change the particle size distribution. System should not cause segregation of coarse and fine particles, nor it should induce static charges. The die feed system must be able to fill the die cavities adequately in the short period of time that the die is passing under the feed frame.
The smaller the tablet , the more difficult it is to get a uniform fill a high press speeds. For high-speed machines, induced die feed systems is necessary. These are available with a variety of feed paddles and with variable speed capabilities. So that optimum feed for every granulation can be obtained. After the die cavities are filled ,the excess is removed by the feed frame to the center of the die table. Compression of the granulation usually occurs as a single event as the heads of the punches pass over the lower and under the upper pressure rollers. This cause the punches to the penetrate the die to a preset depth, compacting the granulation to the thickness of the gap set between the punches.
The rapidity and dwell time in between this press event occurs is determined by the speed at which the press is rotating and by the size of compression rollers. Larger the compressions roller, the more gradually compression force is applied and released. Slowing down the press speed or using larger compression rollers can often reduce capping in a formulation. The final event is ejection of compressed tablets from die cavity. During compression, the granulation is compacted to form tablet, bonds within compressible material must be formed which results in sticking.
High level of lubricant or over blending can result in a soft tablet, decrease in wettability of the powder and an extension of the dissolution time. Binding to die walls can also be overcome by designing the die to be 0. Tablet Coating Sugar coating is carried out in conventional coating pans, has undergone many changes because of new developments in coating technology and changes in safety and environmental regulations. The conventional sugar coating pan has given way to perforated pans or fluidized- bed coating columns.
The development of new polymeric materials has resulted in a change from aqueous sugar coating and more recently, to aqueous film coating. The tablets must be sufficiently hard to withstand the tumbling to which they are subjected in either the coating pan or the coating column. A film coating solution may have been found to work well with a particular tablet in small lab coating pan but may be totally unacceptable on a production scale.
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These measures reduce the potential for contamination ingress into materials that are yet to receive any processing at any site. These areas are designed to minimize the microbial, pyrogen, and particulate contamination to the formulation prior to sterilization. Fill rooms, air locks and gowning rooms are assessed from the corridor. They are fitted with the UltraViolet lights, spray systems, or other devices that may be effectively utilized for decontamination of materials.
WFI is prepared by by distillation or reverse osmosis. Solubilizing agents used in sterile products include: 1. Surface active agents: polysorbate 80, polysorbate 20, lecithin. Complexing agents: cyclodextrins etc They act by reducing the dielectric constant properties of the solvent system, thereby reducing the electrical, conductance capabilities of the solvent and thus increase the solubility. Examples phenol 0. Steps of liquid manufacturing process 1. Planning of material requirements: 2.
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Liquid preparation: 3. Filling and Packing: 4. Tank size diameter 2. Impeller type 3. Impeller diameter 4. Rotational speed of the impeller 5. Number of impellers 6. Number of baffles 7. Mixing capability of impeller 8. Clearance between Impeller Blades and wall of the mixing tank 9. Height of the filled volume in the tank Filteration equipment should not remove active or adjuvant ingredients Transfer system Time and temperature required for hydration of suspending agent 4.
Mixing speeds High speed leads to air entrapment 5. Selection of the equipment according to batch size 6. Versator to avoid air entrapment 7. Mesh size the one which is chosen must be capable of removing the unwanted foreign particulates but should not filter out any of the active ingredients. Such a sieve can only be selected based on production batch size trials. Temperature 2.
Homogenizing equipment 4. Inprocess or final product filters 5. Screens , pumps and filling equipment 6.
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Phase volumes 7. Phase viscosities 8.
Suspensions: Purpose Agent Facilitating the connection between API and -wetting agents vehicle Salt formation ingredients Protecting the API - Buffering-systems, polymers, antioxidants Maintaining the suspension appearance Colorings, suspending agent, flocculating agent. Mixing equipment should effectively move semisolid mass from outside walls to the center and from bottom to top of the kettle 2.
Motors used to drive mixing system and must be sized to handle the product at its most viscous stage. Mixing speed 4. Many of the issues related to the current inefficiency in drug manufacturing originate from the disconnected nature of the processes the industry employs. Current manufacturing practice consists of a series of lengthy and segmented batch process steps often performed in different facilities around the world including isolation, testing, storage and transportation of the various chemical intermediates, as well as the final active pharmaceutical ingredient API. The API is then transported elsewhere to be formulated into the final dosage form, packaged and shipped to distributors.
Also, these series of disconnected steps result in large and expensive inventories. Batch manufacturing introduces a significant lag-time between technical operations such that the cycle time from the start of manufacture to delivery to patients can be as long as 12 months. In addition, a recent analysis conducted by the U. Government Accountability Office found that the number of critical drug shortages has more than tripled since , especially among cancer drugs and nutritional products, and that these shortages were mainly caused by manufacturing problems, sometimes causing manufacturing shutdowns.
The complexity and inefficiency of existing drug manufacturing processes find their roots in the early stages of drug manufacturing process development, where extensive scale-up batches and complex validation procedures are necessary before a new molecular entity can be commercialized, with four major scale-up exercises often being involved bench, kilo, pilot and commercial. Consequently, clinical trial batches may not be representative of final commercial batches such as for the small molecule drug gabapentin, an anticonvulsant and analgesic, which has been subject to several recalls due to new impurities that appeared after scale-up.
Furthermore, the current scenario for quality control during production, which establishes safety and efficacy of a medicament, is not ideal. Although somewhat reliable, this testing protocol leaves significant opportunities for improvement, as demonstrated by the number of post-approval recalls due to quality issues.
A transformation of the pharmaceutical development and manufacturing landscape is necessary, and good examples can be found in the oil, gas and food industries that often run their processes in a substantially different way. In this way, raw materials can be transformed into finished tablets without interruption 24 hours a day , enhancing the performance of the entire process.
This vision of ICM of pharmaceuticals presented in Figure 1 builds on the concepts of continuous flow, end-to-end integration, a systems approach, and an integrated control strategy. In addition, ICM can enable drug manufacturing in smaller facilities with integrated development and manufacturing functions20 and reduced or eliminated product variability associated with scale-up.
Depending on the overall product demand and related economies of scale, pharmaceutical processes could in some cases be simply scaled-out rather than scaled-up. The new ICM plants will be more flexible and able to react more quickly to market changes due to their compact and small-scale characteristics alongside shorter lead time and on-demand production capability. This approach also has important implications during the launch of a new compound where prediction of the actual demand is rarely good.
Economic analyses reported by Schaberet al. Finally, the environmental and social impact should be taken into consideration when transformational technologies are introduced into industries with broad societal impact such as pharmaceuticals. We anticipate that integrated continuous manufacturing of pharmaceuticals can reduce waste generation, as reported in many examples of continuous manufacturing,15 and make pharmaceutical processes safer through confined handing of dangerous chemical reactions and high potency materials. Benyahiaet al. Regulation 3. The work published by the MIT researchers addresses the technology aspect in detail, and also provides a novel approach towards control and modeling, which represents important criteria for regulatory approval of ICM processes.
Indeed, the transition towards ICM poses new challenges for the control of pharmaceutical processes, and mathematical models can play a crucial role from process development to manufacturing in advancing the different operations and reducing costs. An ICM process is characterized by a number of connected unit operations, which pose challenges on deciding where in the process to intervene to improve the critical quality attributes of the final product.
An integrated control strategy is used to address such questions when developing ICM processes. The current batch-to-batch development and manufacturing process, based on the blockbuster model, is costly and inefficient and does not provide the flexibility and quality control necessary for future manufacturing plants. The development of novel manufacturing technologies based on continuous flow can overcome many of these limitations, with Integrated Continuous Manufacturing ICM 16 being the ultimate goal for this industry. Derived from a QbD philosophy and based on a first-principles understanding of the process and the application of concepts as continuous flow, end-to-end integration, systems approach, and integrated control strategy, ICM opens a new avenue for developing and manufacturing pharmaceuticals, where active ingredient and drug product manufacturing are integrated into a seamless process.
ICM can produce high quality, low cost pharmaceuticals in a few days compared to current lead times of 12 months,6 which results from the segmented nature of the batch plant including materials holding, shipping, and off-line testing of chemical intermediates and API. These shorter ICM lead times should also alleviate manufacturing-limited shortages. While science is advancing with the development and fundamental understanding of superior drug manufacturing methods, regulatory agencies and pharmaceutical companies would need to initiate important reorganizations for integrated continuous manufacturing of drugs to be adopted largely within the industry.
Finally, we are also grateful to Novartis for its collaborative effort with MIT in developing the novel continuous manufacturing technologies. Aboud, L. Nickerson, J. Louis, MO. Implementation of the new FDA quality by design guidance in pharmaceutical production. Pharmaceutical Manufacturing ,9 5 , Shah, N.
Comput Chem Eng ,28, Spector, R. Pharmaceutical Manufactuing ,9 7 , Young, S. Burton, T. Shanley, A.