y 1.10 Pilot Plant Scale-Up Technigu, Industrial Phat 4.5 PILOT PLANT SCALE-U! 4.5.1 Pilot Plant Design for Tablets P CONSIDERATIONS FOR SOLIDS ] p and initial production runs. In this extends with the director of nnel in-charge of the that Research pharmacist responsible for initial scale-u type of organizational structure, direct responsibility pharmaceutical research and development and the perso particular department from research. Pharmaceutical pilot plant controlled by pharmaceutical research and scheduling scale- up runs is under the research division control. In this organization, it is the responsibility of the tablet formulator to establish the formulae and manufacturing procedure in pilot plant equipment that should be similar to the production division. Pilot Plant Design for Tablet Development: © The main responsibility of the pilot plant staff is to make sure that the newly formulated tablets developed by product development personnel will prove to be efficiently, economically, and consistently reproducible on a production scale. The design and development of the pharmaceutical pilot plant for tablet development should incorporate features necessary to facilitate maintenance and cleanliness. ‘* It should be located on the ground floor to expedite the delivery and shipment of supplies. * Each stage is considered carefully from experimental lab batch size to intermediate and large-scale production. ‘* Same process, same equipment but different performance when amount of material increased significantly. * May involve a major process change that utilizes techniques and equipment that were either unavailable or unsuitable on a lab scale. 1.5.2 Layout of Pilot Plant Stages of Production of Tablets: © Material handling * Dry blending * Granulation © Drying * Reduction of particle size * Blending * Direct compression * Slugging (dry granulation) 1. Material Handling System: * In the laboratory, materials are simply scooped or transferred by hand, but '? intermediate or large-scale operations, handling of these materials often becom? necessary esIndustrial Pharmacy ~ a 111 Pilot Plant Scale-Up Techniques If a system is used to transfer materials for more than one product, care must be taken to prevent cross contamination. Any material handling system must deliver the specific amount of the ingredient to the formulation. The more sophisticated methods of handling materials are vacuum loading systems, metering pumps, screw feed system, etc. The types of the system selected depend on the nature of the materials, e.g., density and static change. 2. Dry Blending: Inappropriate blending at this stage could result in discrete portion of the batch being either high or low in potency. Measures should be taken to ensure that all the ingredients are free from lumps and agglomerates. For these reasons, screening and/or milling of the ingredients usually makes the process more reliable and reproducible. There are several equipments used in blending process. They are V- blender, double cone blender, Ribbon blender, Slant cone blender, Bin blender, Orbiting screw blenders, vertical and horizontal high intensity mixers, etc. The blending will be optimized by following parameters: 1. Time of blending 2. Blender loading 3. Size of blender 3. Granulation: The purpose of granulation is: To impart good flow properties so that tablet process can be properly fed and uniform tablet weight is maintained. To raise the apparent density of powders. To change the particle size distribution so as to improve the binding properties. Use of granulation processes to disperse an active ingredient is also commonly cited @S a reason to granulate. Traditionally, wet granulation has been carried out using Sigma blade mixer, Heavy-duty Planetary mixer. More recently, the use of “multifunctional processors" that are capable of performing all functions required to prepare a finished granulation such as; dry blending, wet Sranulation, drying, sizing and lubrication in a continuous process in a single equipment. This type is advantageous during scale-up of product i.e. occupies less space, requires limited man power, less material handling and thereby reduce the danger of personnel &xposure to potent materials.112 Pilot Plant Scale-Up Techni = Industrial Pharmacy - It 4, Binders: Binders are either added in dry state and impact their binding properties when exposeg to the granulating solution, so that transfer of the fluid by either pumping or Pouring become difficult. During the scale-up of such a process, problems could be encountereg during the addition of granulating agent to the powders being processed in encloseq equipment. If the problem is anticipated during the formulation stage, the viscosity of the granulating solution can be adjusted so that scale-up problems of this type can be avoided ie, disperse some or all of binding agent in the dry powder prior to granulating. Proper ventilation and additional safety precautions must be considered in the selection and design of equipment and manufacturing area. In some instance, a dough like consistency wet mass will result that may have to be sub divided to more granular and g porous mass to facilitate drying. This can be accomplished by passing the wet mass through an oscillating type granulator with a suitable large screen or a hammer mill with either a suitable large screen or no screen. 5. Drying: The most common conventional method of drying a granulation is to be circulated in hot air oven, which is heated by either steam or electricity. The important factors to be considered 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 will not take place. 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 factors considered as part of scale-up fluidized bed dryer are optimum loads, rate of airflow, inlet air temperature and humidity. 6. Reduction of Particle Size: In this process, the particle size distribution of granulation using a series of “stacked” sieves of decreasing mesh openings is determined. Particle size reduction of the dried granulation of production size batches can be carrie? out by passing all the material through an oscillating granulator, a hammer mill? mechanical sieving device, or in some cases, a screening device. As part of the sale aon oF sieving operation, the lubricants and glidan's io the laboratory are usually a directly to the final blend, This is done because s0™® these additives, especially magnesium stearate, tend to agglomerate when add large quantities to the granulation in a blender, —— lt iEindustrial Pharmacy - I 1.13 Pilot Plant Scale-Up Techniques 7, Blending: type of blending equipment often differs from that using in laboratory scale. In any blending operation, both segregation and mixing occur simultaneously as 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 Variations that may occur in the bulk-density of the raw materials must be considered in selecting a blender and in determining optimum blender load, There is an economic incentive to maximize a batch size, but the maximum batch size to be blended should be conservatively chosen so as to allow latitude for the normal variation in granulation density. &. Dry Blending and Direct Compression: Processes that yield free-flowing granulation without the granulation solutions are desirable. In that, they do not require the time and energy necessary to volatilize the solvent used in conventional wet granulation procedures when exploring the option of direct compression. A careful analysis of particle characteristics, that influence mixing and segregation, such as size distribution, shape and static charge be evaluated. Scaling up a dry blending for operation for a direct compression requires special attentions on blender loads, optimum mixing speeds and the blending time required to assure the drug distribution within the batch acceptable and consistent from batch to batch. Following are the aspects of dry blending operation of directly compressible materials that can be adjusted to optimize the process: * The order of addition of components to the blender: For e.g. low dose active ingredient may be sandwiched between two portions of directly compressible excipient in the blender to improve dispersion and/or to avoid loss to the surface of the blender. * The mixing speed: For e.g. blender rotation speeds for explanatory type mixer and mixes tumbling or rotational speed for a twin - shell, cone type or similar type of mixer. * Mixing time: Can be varied depending upon uniformity. This is also important to compressibility of finished blend. Excessive mixing time may fracture fragile excipients and ruin their compressibility, The use of auxiliary dispersion equipment: The mixer, for e.g. Intensifier bar or chopper blender in a twin-shell mixer to increase efficiency of distribution and reduce aggregation, Mixing action: Differ from blender to blender. Blender load: The amount of material volume to total mixer volume affects efficiency of the blender. Each has an optimum working volume. Excessive load reduces efficiency of the blender while if load is too small, powder slides rather than roling in a blender.Industrial Pharmacy - 114 Pilot Plant Scale-Up Techn) a 9. Slugging (Dry Granulation): This is done on a tablet press designed for slugging, which operates at pressures , about 15 tons, compared with a normal tablet press, which operates at pressure of, tons or less. Slugs range in diameter from 1 inch, for the more easily slugged material, to % inch fp materials that are more difficult to compress, and require more pressure per unit area t; yield satisfactory compacts. If an excessive amount of fine powder is generated during the milling operation the material must be screened and fines are recycled through the slugging operation. 10. 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 o! very low-density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression. Examples of this process are the densification of aluminium hydroxide. 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 o encapsulation properties. 11. Granulation Handling and Feed System: This operation includes handling of finished granulation in the compression area. Thi can be simple operation such as hand scooping or a automated handling system using vacuum or mechanical system to convey the granulation. During scale-up, studies should be undertaken to determine the effect of their additiona handling system on the content uniformity and on the particle size distribution Segregation due to static charges build up during vacuum and or the mechanicé handling of the granulation can lead to problems with material flow through tablet pres hoppers and feed frames. This in turn effects tablet weight, thickness and hardness. P00! content uniformity. The cleaning procedure should be well documented, and validate! for these materials. 12. Compression: During compression, the tablet press performs the following functions: * Filling of empty die cavity with granulates, Optional precompression. Compression of granulation. * Ejection of the tablet from the die cavity and take off compressed tablet. Because of raw material characteristics or formulation constrains, cannot be successfully compressed at the upper speed range oe a and compression characteristics are important factors that must selection of tablet press or speed of compression, ae sx a particular pr a press. The hand be considered '"™ | Pharmacy ~ I 445 Pilot Plant Scale-Up Techniques During scale-up process, while evaluating the compression characteristics of a ee formulation, prolonged trial runs at press speeds equal to that to be used in rer production should be tried, only then potential problems such as sticking to the punc! surface, tablet hardness, capping and weight variation are detected. High speed tablet compression depends on the ability of the press to interact with granulation. The following parameters are optimized during pilot plant techniques of 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 with high press speed. * For high-speed machines, induced die feed systems are 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. * Compression of the granulation usually occurs as a single event as the heads of the punches pass over the lower and the upper pressure rollers. This cause the punches to penetrate the die to a pre-set depth, compacting the granulation to the thickness of the gap set between the punches. During compression, the granulation is compacted to form tablet, bounds 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 wet ability of the powder and an extension of the dissolution time. Binding to die walls can also be overcome by designing the die to be 0.001 to 0.005 inch wider at the upper portion than at the centre in order to relieve pressure during ejection. The machines used are high speed rotary machine, multi-rotary machine, double rotary machine, upper punch and lower punch machine and single rotary machine. 1.5.3 General Considerations () Reporting Responsibilities: Pilot plant functions can be part of a research and development group with separate staffing. (ii) Personnel Requirements: Scientists with experience in pilot plant operations as well as in actual production area are the most preferable. As they have to understand the intent of the formulator as well as understand the perspective of the production personnel. The group should have some personnel with engineering knowledge as well as scale-up also involves engineering principles.Industrial Pharmacy - It 116 ii) (iw) ™) (wi (vii) Pilot Plant Scale-u; Space Requirements: Administration and information process: Adequate of and desk space should be provided for both scientists and technicians. The g should be adjacent to the working area, Physical Testing Area: This area should Provide permanent bench top space fo, routinely used physical-testing equipment. R & D group with separate staff, fice Pace The formulator who developed the product can take it into the Production unit and can provide support even after transition into production has been completed. Storage Area: It should have two areas divided as approved and unapproved area for active ingredients as well as excipients, Separate storage areas should be provided for in-process materials, finished bulk Products from the pilot-plant and materials from the experimental scale-up batches made in the production Storage area for the packing material should also be provided. Review of The Formula: A thorough review of the individual aspect of formulation is important. The purpose of each ingredient and its contribution to the final product manufactured on the small-scale laboratory equipment should be understood. Then the effect of scale-up using equipment that may subject the product to stresses of different types and degrees can more readily be predicted, or recognized. Raw Materials: One purpose/responsibility of the pilot-plant is the approval and validation of the active ingredient and excipients raw materials. Raw materials used in the small-scale production cannot necessarily be the representative for the large-scale production. Equipment: The most economical and the simplest and efficient equipment which are capable of producing product within the proposed specifications are used. The size of the equipment should be such that the experimental trials run should be relevant to the production sized batches. If the equipment is too small, the process developed will not scale-up, whereas if equipment is too big then there may be the wastage of the expensive active ingredients, Production Rates: The immediate as well as the future market trends requirements are considered while determining the production rates. Why to Finished products storag® Quality assurance Techniques 1.1: General Flow Chart of Pilot Plant Scale-u, le-Up