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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5428_Библиотеки_им_академика_М_И_Перельмана
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Steps for Validation and Acceptance Criteria
The following steps used in industry for validation of tablets in wet granulation process are
provided in table 3.55 below.
Table 3.55 Steps for validation and acceptance criteria in wet granulation process.
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Following unit operations are required to be done to manufacture the tablets:
Mixing or Blending of materials
The materials having similar physical properties would be mixed easily to form a
uniform mixture. The mix or blend will not segregate as readily as the materials with
large differences. Parameters to be considered are:
Diffusion (tumble),
Convection (planetary or high intensity), or
Pneumatic (fluid bed) techniques can be used to mix the materials.
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For determination of the formulation or process objective the method of mixing should be
determined. It may be different whether the drug and excipient are to be mixed for making a
directly compressible tablet or a lubricant such as magnesium stearate is to be mixed with
the granules.
Mixing or blending speed
Based on the intensity (low/high shear) the speed (rpm) of the mixing or blending should be
determined. While mixing the drug and excipient, it may require more intense mixing than
adding the lubricant to the final blend.
Mixing or blending duration
The duration of mixing or blending would be determined to obtain a uniform mixture. The
mixing time depends on the mixing or blending method and speed used. Sufficient
experiments should be conducted to determine whether over-mixing, de-mixing or
segregation of the material would take place. Due to difference in physical property such as
particle size distribution and density, de-mixing can occur. For example, if the drug is
micronized having av. particle size of 5µ and the excipients having particle size within 500 –
1000µ are mixed for making directly compressible tablet, de-mixing would occur.
Content uniformity
Uniformity of content is primarily performed to determine whether the drug is uniformly
mixed and uniformly present throughout the mix or blend. Representative samples are drawn
from the mix and the samples are tested individually. The accuracy of results of this test
depends on the sampling method used and handling of materials. During handling
segregation of the materials in the sample may take place and may result in inaccuracy of the
results. As regards the final blend (blend before compression), the weight of each sample is
equivalent to the weight of a single tablet.
Excipient uniformity
Not only the drug should be uniformly distributed in the mix; the excipients need to be
uniformly distributed in the granulation or blend. Particularly two key excipients must be
uniformly mixed. These are:
Lubricant : The lubricant must be uniformly distributed in the mixture/granulation for
the high-speed compression operation. Otherwise, picking and sticking can occur
during compression. It can also lead to the performance problems of the tablet such as
low dissolution due to excessive lubricant in some tablets.
Color : The appearance of a tablet becomes uniform when colorant(s) are evenly
distributed in the mixture. Otherwise, speckling or shading of the color can occur. The
intensity and uniformity of the color depend on the amount and uniform mixing of the
color(s).
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Equipment capacity/load
The bulk density of materials or granules can affect the capacity of the equipment used. If an
excipient in the formulation influences 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
required. For optimal mixing or blending, testing of different-sized loads in the
mixer/blender (e.g., 30, 50, and 70% of working volume) is also necessary. In case of
undercharging or overcharging, a blender can result in poor drug or tablet lubricant
distribution.
Table 3.56 Check list of validation and control documentation
Sl.NoParameters as per cGMP Validation and control documentation
1 Introduction Establishment of Quality Assurance and
Product Verification functions
2 Organization and personnel Establishment of facility installation and
qualification
3 Buildings and facilities Plant and facility installation qualification
Maintenance and sanitation
Microbial and pest control
4 Equipment Installation and qualification of cleaning
methods
5 Air and water quality Water treatment and steam systems Air, heat,
and vacuum handling.
6 Control of raw material,
inprocess material, product
Incoming components
Manufacturing non-sterile products
7 Production and process controls Process control systems (instruments and
computers)
8 Packing and labeling controls Depyrogenation, sterile packing, filling, and
closing.
9 Holding and distribution Facilities
10 Laboratory controls Analytical methods
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11 Records and reports Computer systems
12 Returned and salvage drug
products
Batch processing
Wet Granulation
Before proceeding to wet granulation following questions should come into mind and proper
answer to each question should be noted down.
What type of wet granulation technique will be used?
Will it be low shear such as Hobart, high shear such as Diosna, GEI-Collette or fluid
bed such as Glatt, Fluid Air?
Granules with different physical properties will be produced in each technique. Each
technique will require monitoring of different processing parameters. Wet granulation
parameters to be considered during development and validation stages are:
Addition of binder: Is the binder added as a granulating solution or in form of dry
powder like the other excipients? Addition of the binder in dry form avoids the need to
determine the optimal binder concentration and a separate manufacture for the binder
solution.
Binder concentration: It is necessary to determine the optimal concentration of the
binder for the formulation. If the binder solution is to be sprayed, the solution should
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: It is necessary to know the quantity
of binder or solvent solution would be required to granulate the material. If the binder
or solvent solution added is too much, it will over-wet the materials and prolong the
drying time. The amount of binder solution added and the binder concentration are
related to each other.
Rate of the binder solution/granulating solvent: The rate at which the binder
solution or granulating solvent is to be added to the materials should be determined. In
this case, following question should be raised. Can the granulating solution be dumped
into the mixer, or does it have to be metered-in at a specific rate?
Mixing time: It is also essential to know the duration of mixing of the material 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 of
the granulation can result in harder granules and a lower dissolution rate.
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Granulation end point: To prepare the granules of desired strength and to achieve
adequate dissolution rate, the granulation end point should be determined. Can it be
determined or controlled by granulation end point equipment such as ammeter or
wattmeter or by specifying critical processing parameters? 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 pre-set time
after the water has been added.
Wet Milling: Sometimes, the wet granulation needs 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 be considered 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 to prevent the material from drying during this
operation.
Screen size
The screen should be small enough to delump the material, but not too small to cause
excessive heating of the mill, so that it causes drying of the granulation.
Mill speed
The speed of the mill should be sufficient so that it can efficiently delump the material
without straining the equipment.
Feed rate
The feed rate of the wet granulation is related to size of the screen, mill size and its speed.
Drying
The type of drying technique such as tray dryer, fluidized bed dryer, and microwave required
for the formulation needs to be determined and justified. The type of technique may depend
on such factors as properties of the drug or formulation and availability of equipment.
Changing the dryer could affect the properties of tablet such as hardness, disintegration,
dissolution, and stability. The optimal moisture content of the dried granulation should be
determined. High moisture content can result in (1) picking of tablet or sticking of tablet to
punch surfaces, and (2) hydrolysis due to poor chemical stability. An over dried granulation
could result in poor hardness and friability.
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Moisture content can be determined using the conventional loss-on-drying methods or by
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 dryer. The inlet temperature is important for the
drying efficiency of the granulation and should be adjusted high enough to maximize drying
without affecting the physicochemical stability of the granulation. The outlet temperature
indicates the granulation temperature and will increase with the inlet temperature as the
moisture content of the granulation decreases (rate of evaporation).
Airflow
There should be sufficient airflow to ensure removal of moisture carrying air from the wet
granulation. Insufficient airflow could delay 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. Uniformity in moisture content of
the granules depends on
heat uniformity of the dryer such as tray dryer,
the amount of granulation per tray, and
incomplete fluidization of the bed.
If these are not properly controlled, the moisture uniformity of the granulation shall be
affected.
Equipment capability/capacity
The quantity of material (load) that can be efficiently dried within a particular dryer should
be known. If the dryer contains a larger load, it will require more moisture to be removed
during drying and thus, the drying time increases. In the case of fluid bed drying, a
maximum dryer load is that load above which the dryer will not fluidize the material.
Milling
The milling operation reduces the particle size of the dried granulation. The resultant particle
size distribution can affect the properties of material such as its flow property,
compressibility, disintegration, and dissolution. An optimal particle size/size distribution for
the formulation will need to be determined. Factors to be considered in milling are:
Mill type
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Whatever the type of mill such as impact or screen is used; each has several variants,
depending on how the particles are being reduced. Thus, depending on the type of mill,
different particle size/size distribution can be produced. Particle size testing will require to
be conducted and the results examined when substituting the types of mills.
Screen size
The screen size selected for use will affect the particle size. A smaller screen size will
produce a smaller particles, and a greater number of fines.
Mill speed
The optimal mill speed should be determined. A higher mill speed will produce smaller
particles and perhaps 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 rate, at which the mill is fed, is dependent on the capacity of the mill, screen size, and
mill speed.
Lubrication
Selection of lubricant
The kind of lubricant used, should be of a suitable grade. The lubricant should be compatible
with other ingredients also.
Amount of lubricant added
Too much of lubricant will form hydrophobic layer on the tablet and will create problems in
dissolution.
Mixing time
The material should be mixed with lubricant to ensure proper formation. It is also necessary
to know whether mixing should be stopped after the addition of the lubricant or there should
be additional mixing required. Mixing for long do not cause problems like chipping,
capping, etc.
Tablet Compression
In fact, compression is a critical step in the production of a tablet dosage form. The materials
being compressed should possess adequate flow property and also adequate compressibility.
Thus, the material should freely flow from the hopper onto the feed frame and into the dies.
Inadequate flow can produce “rat holing” in the hopper and/or segregation of the blend in
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the hopper/feed frame. This can cause problems in the tablet weight and content uniformity.
The compressibility properties of the formulation should be examined on an instrumented
tablet press. Factors to be considered 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 embossed tablets, the factors such as the
position of the embossing on the tablet and the depth and style of embossing should be
examined to be sure that picking of the embossing during compression or fill-in of the
embossing during coating does not take place.
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. A force feeder may be required to ensure
that sufficient material is fed into the dies.
Compression/ejection force
The compression profile for the tablet formulation should be determined to establish the
optimal compression force required to obtain the desired tablet hardness. The particle
size/size distribution or level of lubricant should be adjusted to have a robust process on a
highspeed compressor. The following in-process tests should be performed during the
compression stage to examine:
Appearance
Hardness
Tablet weight
Friability
Disintegration
Weight uniformity
Tablet Coating
Tablet coating can be done by different methods such as sugar, film, or compression. Film
coating has been the most common technique in recent years and will be the focus of this
section.
Important areas to be considered for tablet coating are:
Tablet properties
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Tablet properties such as hardness, shape, and embossing (if required) are important to
obtain a good film-coated tablet. The tablet should be hard enough to withstand the coating
process. If attrition to tablet occurs, the tablets will have a rough surface appearance. For
good tablet shape, a round tablet will be easier to coat than tablets with multiple sides or
edges because of the uniformity of the surface. For embossed tablets, the style of embossing
and its depth should be developed to prevent fill-in or chipping of the embossing.
Equipment type
The type of coater should be selected first. Conventional or perforated pan and fluid bed
coaters are potential options.
Coater load
The acceptable tablet load range of the equipment should be known before start of the
coating operation. Using too large 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
The speed of the pan should be optimal. 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 to coat the tablets efficiently. The size
of spray nozzles should be proper to distribute the coating solution evenly over the tablet bed
and to prevent clogging of the nozzles. The location and angle of the spray guns should be
positioned to get adequate coverage. If the positions of the guns are too close together, a
portion of the tablets become over wet.
Application/spray rate
The optimal application/spray rate should be determined. Spraying too fast will cause the
tablets to become over wet and the tablets form cluster. Possibly, this causes the dissolution
of the tablet surface. Spraying too slowly will cause the coating materials to dry before
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 coating pan should be examined to make sure of
the proper flow. There should be sufficient movement of the tablet bed for even distribution
of the coating solution onto the tablets. The baffles may be required to provide adequate
movement of tablets for tablet coating.
Inlet/outlet temperature and airflow
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