Friday, December 17, 2010


Determine the unit operations needed to manufacture the tablets.
1. Mixing or Blending:
Materials that have similar physical properties will be easier to form a uniform mix or blend and will not segregate as readily as materials with large differences.
Parameters to consider:
·         Mixing or blending technique: Diffusion (tumble), convection (planetary or high intensity), or pneumatic (fluid bed) techniques can be used to mix or blend materials. Determine the technique that is required for the formulation or process objective. It may be different, depending on whether you are mixing the drug and excipient for a direct compression formulation or adding the lubricant (e.g., magnesium stearate) to the granulation.
·         Mixing or blending speed: Determine the intensity (low/high shear) and/or speed (low/high/optimal shear) (rpm) of the mixing or blending. Mixing the drug and excipient will require more intense mixing than adding the lubricant to the final blend.
·         Mixing or blending time: How much mixing or blending is required to obtain a uniform mixture? The mixing or blending time will be dependent on the mixing or blending technique and speed. Experiments should be done to determine if the materials can be over mixed, resulting in demixing or segregation of the materials. Demixing can occur due to the physical property differences (e.g., particle size distribution and density). For example, demixing can occur in a direct compression formulation in which the drug substance is micronized (5 microns) and the excipient are granular (500–1000 microns).
·         Drug uniformity: Content uniformity is usually performed to determine the uniformity of drug throughout the mix or blend. Representative samples should be taken throughout the mix or blend. The sampling technique and handling of the materials are key in obtaining valid content uniformity results. Segregation of the sample can occur by over handling, resulting in inaccurate results. For the final blend (blend prior to compression), the sample taken should be equivalent to the weight of a single tablet.
·         Excipient uniformity: Besides drug uniformity, excipient needs to be uniform in the granulation or blend. Two key excipient are:
R      Lubricant: The lubricant needs to be distributed uniformly in the mixture/granulation for the high-speed compression operation. Uneven distribution of the lubricant can result in picking and sticky problems during compression. It can also lead to tablet performance problems (low dissolution due to excessive lubricant in some tablets).
R      Color: The colorant(s) need(s) to be evenly distributed in the mixture so that the tablets have a uniform appearance (e.g., color, hue, and intensity). The coloring agent may need to be prescreened or more uniformly dispersed in the blend prior to compression to avoid speckling or shading of the color.
·         Equipment capacity/load: The bulk density of materials or granules will affect the capacity of the equipment. If an excipient in the formulation affects the density of the final blend to a greater extent than any other ingredient, then a well-controlled density specification for that excipient may be warranted. Test different-sized loads in the mixer/blender (e.g., 30, 50, and 70% of working volume) for optimal mixing or blending. Undercharging or overcharging a blender can result in poor drug or tablet lubricant distribution.
2. Wet Granulation
What type of wet granulation technique will be used? Will it be low shear (e.g., Hobart), high shear (e.g., Diosna, GEI-Collette) or fluid bed (e.g., Glatt, Fluid Air)? Each technique will produce granules with different physical properties and will require monitoring of different processing parameters. Wet granulation parameters to be considered during development and validation are:
·         Binder addition: Should the binder be added as a granulating solution or dry like the other excipient? Adding the binder dry avoids the need to determine the optimal binder concentration and a separate manufacture for the binder solution.
·         Binder concentration: The optimal binder concentration will need to be determined for the formulation. If the binder is to be sprayed, the binder solution needs to be dilute enough so that it can be pumped through the spray nozzle. It should  also be sufficiently concentrated to form granules without over wetting the materials.
·         Amount of binder solution/granulating solvent: How much binder or solvent solution is required to granulate the material? Too much binder or solvent solution will over wet the materials and prolong the drying time. The amount of binder solution is related to the binder concentration.
·         Binder solution/granulating solvent addition rate: Define the rate or rate range at which the binder solution or granulating solvent can be added to the materials. Can the granulating solution be dumped into the mixer or does it have to be metered in at a specific rate?
·         Mixing time: How long should the material be mixed to ensure proper formation of granules? Should mixing stop after the addition of the binder or solvent solution or should additional mixing be required? Granulations that are not mixed long enough can form incomplete or weak granules. These granules may have poor flow and compression properties. On the other hand, over mixing the granulation can lead to harder granules and a lower dissolution rate.
·         Granulation end point: How is the granulation end point determined? Is it determined or controlled by granulation end point equipment (e.g., ammeter or wattmeter)? Is it controlled by specifying critical processing parameters? For example, a drug or excipient mixture may be granulated by adding a predetermined amount of water (granulating solution) at a certain rate. The granulation is completed after mixing for a set time after the water has been added.
3. Wet Milling
Does the wet granulation need to be milled to break up the lumps and enhance drying of the granulation? Wet granules that have a wide aggregate range can lead to inefficient drying (long drying times and partially dried large granules or lumps). Factors to consider are:
·         Equipment size and capacity: The mill should be large enough to delump the entire batch within a reasonable time period to minimize manufacturing time and prevent the material from drying during this operation.
·         Screen size: The screen needs to be small enough to delump the material, but not too small to cause excessive heating of the mill, resulting in drying of the granulation.
·         Mill speed: The speed should be sufficient to efficiently delump the material without straining the equipment.
·         Feed rate: The feed rate of the wet granulation is interrelated to screen size and mill size and speed.
4. Drying
The type of drying technique (e.g., tray, fluid bed, and microwave) required for the formulation needs to be determined and justified. The type of technique may be dependent on such factors as drug or formulation properties and equipment availability. Changing dryer techniques could affect such tablet properties as hardness, disintegration, dissolution, and stability. The optimal moisture content of the dried granulation needs to be determined. High moisture content can result in
(1) Tablet picking or sticking to tablet punch surfaces and 
(2) Poor chemical stability as a result of hydrolysis.
An over dried granulation could result in poor hardness and friability. Moisture content analysis can he performed using the conventional loss-on-drying techniques or such state-of-the-art techniques as near infrared (NIR) spectroscopy.
·         Inlet/outlet temperature: The inlet temperature is the temperature of the incoming air to the dryer, while the outlet temperature is the temperature leaving the unit. The inlet temperature is critical to the drying efficiency of the granulation and should be set high enough to maximize drying without affecting the chemical/physical stability of the granulation. The outlet temperature is an indicator of the granulation temperature and will increase toward the inlet temperature as the moisture content of the granulation decreases (evaporization rate).
·         Airflow: There should be sufficient airflow to ensure removal of moisture laden air from the wet granulation. Insufficient airflow could prolong drying and affect the chemical stability of the drug. Airflow and the inlet/outlet temperature are interrelated parameters and should be considered together.
·         Moisture uniformity: The moisture content could vary within the granulation. Heat uniformity of the dryer (e.g., tray), amount of granulation per tray, and incomplete fluidization of the bed are factors that could affect the moisture uniformity of the granulation.
·         Equipment capability/capacity: The load that can be efficiently dried within the unit needs to be known. A larger load will require more moisture to be removed
·         on drying and will affect the drying time. In the case of fluid bed drying, a maximum dryer load is that load above which the dryer will not fluidize the material.
5. Milling
The milling operation will reduce the particle size of the dried granulation. The resultant particle size distribution will affect such material properties as flow, compressibility, disintegration, and dissolution. An optimal particle size/size distribution for the formulation will need to be determined. Factors to consider in milling are:
·         Mill type: What mill type (e.g., impact or screen) should be used? Each has several variants, depending on the means to reduce the particles. The type of mill can generate a different particle size/size distribution. Particle size testing will need to be conducted and the results examined when substituting mill types.
·         Screen size: The selected screen size will affect the particle size. A smaller screen size will produce a smaller particle size and a greater number of fines.
·         Mill speed: What is the optimal mill speed? A higher mill speed will result in a smaller particle size and possibly a wider particle size distribution. It can also generate more heat to the product, depending on the screen size and feed rate, which could affect the stability of the product.
·         Feed rate: The feed rate is dependent on the mill capacity, screen size, and mill speed.
6. Lubrication
Selection of lubricant:  what kind of lubricant should be used? Grade of the lubricant used. Compatibility with other ingredients. Amount of lubricant added:  How much lubricant is required? Too much lubricant will form hydrophobic layer on the tablet resulting in dissolution problems. Mixing time:  How long should the material is mixed to ensure proper formation? Should mixing stop after the addition of the lubricant or should additional mixing be required? If not mixed long enough form problems like chipping, capping, etc.
7. Tablet Compression
Compression is a critical step in the production of a tablet dosage form. The materials being compressed will need to have adequate flow and compression properties. The material should readily flow from the hopper onto the feed frame and into the dies. Inadequate flow can result in “rat holing” in the hopper and/or segregation of the blend in the hopper/feed frame. This can cause tablet weight and content uniformity problems. As for the compressibility properties of the formulation, it should be examined on an instrumented tablet press. Factors to consider during compression are as follows:
·         Tooling: The shape, size, and concavity of the tooling should be examined based on the formulation properties and commercial specifications. For intagliated (embossed) tablets, factors such as the position of the intagliation on the tablet and the intagliation depth and style should be examined to ensure that picking of the intagliation during compression or fill-in of the intagliation during coating does not occur.
·         Compression speed: The formulation should be compressed at a wide range of compression speeds to determine the operating range of the compressor. The adequacy of the material’s flow into the dies will be determined by examining the tablet weights. Is a force feeder required to ensure that sufficient material is fed into the dies?
·         Compression/ejection force: The compression profile for the tablet formulation will need to be determined to establish the optimal compression force to obtain the desired tablet hardness. The particle size/size distribution or level of lubricant may need to be adjusted in order to have a robust process on a high-speed compressor.
      The following in-process tests should be examined during the compression stage:
      1.  Appearance
      2.  Hardness
      3.  Tablet weight
      4.  Friability
      5.  Disintegration
      6.  Weight uniformity

8. Tablet Coating
Tablet coating can occur by different techniques (e.g., sugar, film, or compression). Film coating has been the most common technique over recent years and will be the focus of these section Key areas to consider for tablet coating include the following:
·         Tablet properties: Tablet properties such as hardness, shape, and intagliation (if required) are important to obtain a good film-coated tablet. The tablet needs to be hard enough to withstand the coating process. If tablet attrition occurs, the tablets will have a rough surface appearance. For tablet shape, a round tablet will be easier to coat than tablets will multiple sides or edges because of the uniformity of the surface. For intagliated tablets, the intagliation style and depth should be developed to prevent fill-in or chipping of the intagliation.
·         Equipment type: The type of coater will need to be selected. Conventional or perforated pan and fluid bed coaters are potential options.
·         Coater load: What is the acceptable tablet load range of the equipment? Having too large a pan load could cause attrition of the tablets because of the overall tablet weight in the coater. In the case of a fluid bed coater, there may not be sufficient airflow to fluidize the tablets.
·         Pan speed: What is the optimal pan speed? This will be interrelated to other coating parameters, such as inlet temperature, spray rate, and flow rate.
·         Spray guns: The number and types of guns should be determined in order to efficiently coat the tablets. The spray nozzles should be sized properly to ensure even distribution over the tablet bed and to prevent clogging of the nozzles. The location and angle of the spray gun(s) should be positioned to get adequate coverage. Having the guns positioned too close together can lead to a portion of the tablets to be over wet.
·         Application/spray rate: The optimal application/spray rate should be determined. Spraying too fast will cause the tablets to become over wet, resulting in clumping of tablets and possible dissolution of the tablet surface. Spraying too slowly will cause the coating materials to dry prior to adhesion to the tablets. This will result in a rough tablet surface and poor coating efficiency.
·         Tablet flow: The flow or movement of the tablets in the coater should be examined to ensure proper flow. There should be sufficient tablet bed movement to ensure even distribution of the coating solution onto the tablets. The addition of baffles may be required to provide adequate movement of tablets for tablet coating.
·         Inlet/outlet temperature and airflow: These parameters are interrelated and should be set to ensure that the atomized coating solution reaches the tablet surface and then is quickly dried.
·         Coating solution: The concentration and viscosity of the coating solution will need to be determined. The solution will need to be sufficiently diluted in order to
·         Spray the material on the tablets. The concentration of the coating solution will also determine the amount and volume of solution to be applied to the tablets. The stability of the coating solution should be investigated to establish its shelf life.
·         Coating weight: A minimum and maximum coating weight should be established for the tablet. Sufficient coating material should be applied to the tablets to provide a uniform appearance; however, it should not be great enough to cause fill-in of the intagliation. 
·         Residual solvent level: If solvents are used for tablet coating, the residual solvent level will need to be determined. Appearance testing of the tablets is critical during the coating operation. Items to look for include the following:
1.  Cracking or peeling of the coating 
2.  Intagliation fill-in
3.  Surface roughness
4.  Color uniformity
5. Coating efficiency should be determined for the coating operation. The efficiency will determine the amount of coating solution overage that may be required.
9. In-process tests
1.  Moisture content of “dried granulation”
2.  Granulation particle size distribution
3.  Blend uniformity
4.  Individual tablet/capsule weight
5.  Tablet hardness
6.  Tablet thickness
7.  Disintegration
8.  Impurity profile
10. Finished product tests
1.  Appearance
2.  Assay
3.  Content uniformity
4.  Tablet hardness
5.  Tablet friability
6.  Impurity profile
7.  Dissolution
These key test parameters are the yardsticks by which the major processing variables in solid dosage forms are evaluated. Some processing variables are:
·         Mixing time and speed in blenders and granulators
·         Solvent addition rates in granulators
·          Time, temperature, and airflow conditions in dryers and coaters
·          Screen size, feed rate, and milling speed in mills
·         Machine speed and compression force in tablet presses
Process validation testing is generally done on the first three batches of product made in production-size equipment. Revalidation testing is only done when a “significant” change has occurred. A significant change is one that will alter the in-process or final product specification established during the validation program or a change in formula, process, or equipment.

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