Quality by Design (QbD) refers to a holistic approach towards drug development. It was confirmed that the use of multivariate methods, defined as (QbD) values and tools in ICH-Q8 guidance, provides an effective means to accomplish a greater understanding of tablet dissolution upon stability.( Maltesen, 2008, Huang, 2010)
QbD encompasses the idea of tools such as: critical quality attributes (CQAs); design of experiment (DOE); risk assessment; and process analytical technology (PAT) to the expansion of pharmaceuticals.( Verma et al, 2009 , Huang, 2010).The significant role of PAT in a booming QbD environment is acknowledged, providing an overview of important multivariate mathematical techniques and modern analytical technologies for process monitoring that facilitate process understanding and ultimately process control. The concept of design space is considered, describing the relationship between critical process parameters (CPPs) and critical quality attributes (CQAs). The FDA's Process Analytical Technology (PAT) proposal is anticipated to advance pharmaceutical process identification, simulation, and control PAT is a method for designing, analyzing, and controlling manufacturing throughout timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.
Ref: Basu, P., 2009
A Simple Flow Diagram (SFD) is as follows:
Ref: Bennett & Coleman, 2003
Dry Granulation Process:
Granulation is a particle design process whereby small particles are brought together to form physically strong agglomerates. It forms granules by light compaction of the powder blend beneath low pressures. The compacts so-formed are broken up lightly to produce granules (agglomerates). It can be used on a tablet press using slugging tooling or on a roll press called a roller compactor.
Purpose of each stage:
During dry granulation process the dry powders of the active ingredient and excipients, e.g., dry binders, disintegrants, diluents and lubricants, are mixed in a blender. The powder mixtures are then roller compacted and milled to form granules. The resulting granulation is normally blended with a lubricant and either encapsulated or compressed into a tablet. The compaction of powder by means of pressure roll can also be accomplished by a machine called chilsonator. Unlike tablet machine, the chilsonator turns out a compacted mass in a steady continuous flow. The powder is fed down between the rollers from the hopper which contains a spiral auger to feed the powder into the compaction zone. Like slugs, the aggregates are screened or milled for production into granules.
Ideal characteristics of granules:
The effectiveness of granulation depends on following properties:
Particle size of the drug and excipients
Type of binder (strong or weak)
Volume of binder (less or more)
Wet massing time ( less or more)
Amount of shear applied to distribute drug, binder and moisture.
Drying rate ( Hydrate formation and polymorphism
Advantages:
It uses less equipments and space
For moisture & heat sensitive material
For improved disintegration as powder particles are not bonded collectively by a binder.
Disadvantages:
It requires a specialized heavy duty tablet press to form slug.
It does not permit uniform colour distribution as can be accomplished with wet granulation where the dye can be incorporated into binder liquid.
The process tends to form more dust than wet granulation, increasing the potential contamination.
Roller compaction:
In case of pharmaceutical industry, roller compaction is a unit operation in the dry granulation process, a commonly used pressure-induced agglomeration technique in which granules with acceptable flowability, compositional uniformity, compaction properties, and chemical stability are formed from feed material consisting of mixtures of active and excipient (inert) powders.
During roller compaction, the powder mixture is constantly fed - often with the aid of a screw feeder - to two counter-rotating rolls, which draws the powder between the rolls and compacts the powders into strips or flakes of compacted material. The feed powder is densified by a combination of shear and hydrostatic stresses that expand from the feed stress, friction at the rolls and the confining limitations, i.e., rolls, screw and lateral side seals. This process produces a ribbon, sheet or briquette, which can be milled to yield the desired granule particle size.
Active drug Excipients Roll compaction Milling Tabletting
General Operational Principles:
Typical roller compaction processes consist of the following steps:
â- Convey powdered material to compaction area (normally with screw feeder);
â- Compact powder between two counter-rotating rolls with applied forces;
â- Mill compact (sheet, flake or briquette) to desired particle size distribution.
Roller compaction can handle cohesive powders of changeable consistency
• Aim is to enhance particle size so that powders flow
• Aim to coalesce powders to avoid segregation
Ref: americanpharmaceuticalreview.comst Point, PA, 2Roland Research Devices, Inc., Trenton, NJ
Compaction process details:
Slip zone
Deaeration of the powder occurs in this region.
Powder is enforced into the gap between the rolls via a sliding motion that results from the rotation of the feed screw and roll surfaces.
Internal friction coefficient of powder determines the size of the slip zone (larger coefficient - smaller slip zone - longer compaction time).
Nip zone
Defined by the nip angle which is determined theoretically by the compression factor, internal friction angle and roll/powder friction angle.
Starts where no slippage of powder occurs at the roll surface.
Powder is carried into the roll gap at the similar speed as the roll surface.
To accomplish acceptable compaction, the nip angle must be huge or residence time in the nip zone must be improved to permit particle bonding to happen.
Release zone
Elastic recovery (expansion) of the compacted sheet occurs as it is free from the rolls.
Extension of the compact is a function of physical characteristics of the material, roll speed, and roll diameter.
More efficient deaeration of powder reduces the expansion due to superior bond formation (conversion to plastic deformation as opposed to elastic).
A successful process based on roller compaction followed by milling should produce a granule with consistent particle size distribution, density, and porosity control.
Roller Compaction: Advantages
Binder-less agglomeration
Dry - therefore suitable for moisture and heat-sensitive materials can be processed
Simple process (no wetting or drying steps)
Continuous process
Readily scale able: Everything linear.
Decreases unacceptable elastic recovery
Amenable to PAT
Drug and color migration do not occur
Shorter disintegration times can be obtained (if no binder is used)
Less equipment, cost, and space are required
Reasons to use Roller Compaction:
No or low dust, increased safety when working with toxic or explosive materials
Improved flow characteristics
No segregation of components; increased bulk density
Increased particle size
Equipment variables:
Rolls mounted horizontally, vertically or inclined
Roll diameter
Roll width
Feeding system:
Gravity vs. screw feeder
Powder de-aeration unit
Two fixed rolls vs. one fixed and one movable roller
Critical Process Parameters:
Roll Compaction pressure/specific compaction force (i.e. compaction force per cm of roll width)
Speed of feeding screws (vertical vs. horizontal) or Feed screw rate(speed)
Roll speed
Roll Gap/ Separation
Milling Conditions ( i.e. room temperature and humidity)
CPP can be efficient in terms of volume in and volume out.
Ref: Mansa et al., 2008
Impact of critical process parameters:
Even with suitable roller compactor and parts, roller compaction process parameters have very considerable effects on process feasibility, granule tablet ability and ribbon quality. Compaction force, roll speed, and feeder screw speed are the critical parameters needed to be optimized to improve product quality.
Roll speed
Faster roll speed means faster throughput--Normally rollers have feedback loop to feeders
Plastic materials will deform more the slower the roll speed
Impact of changing roll speed on densification dependent on material properties of feed stock.
Brittle materials less apt to be exaggerated by slower roll speed, but rollers are obtainable so slowly that strain rate effects generally do not occur.
It controls the dwell time of the compact and ultimately the throughput of the roller compactor.
The selection of roll speed depends on the flowability, elasticity, and plasticity of the powder.
Ref: Gupta et al, 2003
Screw speed
For equipment with force feeding, screw speed is a important process parameter to achieve high granule quality.
The force produced by a rotating flight generates a downward compression force that not only forces the powder into the compaction zone but also pre-densifies the powder.
Compaction force
A lowest compaction force is needed to compress the loose powder into ribbons.
As described earlier, under pressure, solid particles densify, deform or fracture, and bond to form ribbons.
At a higher compaction force, stronger compact with a lower porosity and less fine is produced. (Pitt, K., 2009)
Critical to Quality Attributes:
Ribbon Density, strength and thickness caused due to roll force/pressure
Ribbon/particle size and shape caused by roll gap/separation
Appearance caused due to roll speed
Change in porosity caused due to addition of binders
Granule density and granule porosity
Particle size distribution
Ribbon porosity
Ref: Mansa et al., 2008
Particle size, zeta potential and the physical form of the drug constituted the critical quality attributes (CQAs).ck & Co., I
Process control:
Usually only 2 out of the 3 parameters of roll pressure roll gap and feed-rate can be set in any control loop.
There are 3 controllable parameters: roll pressure, roll gap (or, when without gap control, ribbon thickness that can be controlled by feed screw speed), and roll speed.
3rd variable will then float to meet the other 2 set parameters.
E.g. if set gap of 2mm and set pressure of 40MPa, then screw feed rate will be varied by control loop.
Roller Compaction: Disadvantages
Potential for high amount of re-cycle or reprocessing
Possible loss of tablet compressibility
Limitations in colour variety
Dissolution can be adversely affected, due to densification
Powders must be compressible (if primary product powder is not compressible, then a compressible component should be added to the formulation), typically requires the addition of a lubricant to lower sticking to the rolls.
Roller compaction: Rationalization
Densification = Volume in/volume out
The greater volume change, the greater the densification
Mass in and out remains constant in a unit time
Hence Density (or Solid Fraction) is key factor being changed (Solid fraction = Envelope Density ÷True Density)
Solid Fraction during Roller Compaction:
Ref: Teng et al., 2009
Dry Binders
One important prerequisite for a dry binder is good powder flowability. The dry binding character are prejudiced by powder's morphology, shape and size, plasticity, porosity, compressibility , hygroscopicity, moisture & heat ,stability to air, and compatibility with APIs.
Binding agents are frequently incorporated into dry granulation formulations to improvise granule and tablet strength. Tablet binding agents added during dry granulation techniques are called 'pressure binders. The stronger binding uniqueness are governed by intermolecular forces and mechanical interlocking, depending upon the excipients type. The role of binders is to agglomerate drug substance and excipients to form improved granules with suitable density, particle size distribution, strength, & thus tablets with tolerable friability. At low binder levels, there are not enough binders to cover particle surfaces. Consequently, even though ribbons may be formed after roller compaction, the strength and particle size control of granules can be very poor. On the other hand, if the binder level is too high, tablet disintegration and dissolution may suffer. Smaller binder particles with a larger surface area give better surface coverage of other ingredients, thus enhance the binder efficiency, e.g. cellulose and starch derivatives, PVP, etc. Many cellulose and starch derivatives have been used as binders in roller compaction. These binders include methylcellulose, ethylcellulose, hypromellose (hydroxypropyl methylcellulose), HPC (hydroxypropylcellulose), pregelatinized corn starch, and MCC (microcrystalline cellulose). (Teng et al.,2009)
Filler
The primary function of fillers is to ease formulation design and process development. Fillers play a vital role in modifying the pre-compaction blend properties to accomplish desirable compatibility, flow, and density. For a very plastic or brittle drug substance, the choice of filler may be the most significant step in formulation design. By balancing the plasticity/elasticity/brittleness of the pre-compaction powder, fillers are significant in making roller compression process feasible and in ensuring good ribbon and granule quality.
Excipient/granule particle size
Usually, fine particles show enhanced compatibility than coarse particles. The effects of particle size on compaction properties are more outstanding for plastic materials than for brittle materials. This effect can be best explained by particle bonding theory. Excipients play a major role in the development of robust formulations because they can influence the degree of granule compression and binding and can also absorb mechanical stress derived from the granulation and tableting processes without affecting tablet hardness and tensile strength.
Glidant
They are added to a great number of roller compaction formulations to develop the flow ability of pre-compression powder. They act as ball bearings to decrease the friction among particles.
Lubricant
Its function is to lessen the friction between contacting equipment surface and granule/tablets. Lubrication is analogous to coating process. Lubricants can form thin films on particle surfaces, thus modifying the interaction between solid bulks and contacting equipment surface. Intragranularly, lubricants reduce the friction between ribbon and rolls, whereas extra granularly, lubricants decrease the friction between tablets and die walls.
Disintegrant
A disintegrant is used to break tablets into granules and further into fine particles, and to achieve satisfactory disintegration time and dissolution rate. Thus, proper control of ribbon and granule porosity can lead to improved disintegration efficiency. Here, disintegrants can be used in both intragranular and extragranular portions. ( Teng et al.,2009)
Ref: Basu, P., 2009
Design Space:
Purpose:
Roller compaction [dry granulation] has gained popularity throughout the pharmaceutical industry. One goal of roller compaction is to improve compressibility and yield repeatable tablet dissolution and content uniformity. To ensure downstream process and product consistency, a successful roller compaction process establishes a continuous flow with a consistent particle size distribution. However, inconsistencies often occur during dry granulation scale up due to changing raw materials or process dynamics such as segregation, compaction force, and flow properties. The application of FBRM®, in-situ particle characterization, is demonstrated to map the design space and optimize a series of roller compaction runs while varying raw materials, flow rates, and roller compaction forces. FBRM® allows a user to directly link process control parameters to the particle distribution and the product performance. By designing a robust roller compaction process one can ensure consistent downstream processing from dry granulation through tablet compression.
METTLER TOLEDO C35 FBRM probe monitors roller compaction in real time
Ref: http://blog.autochem.mt.com
Methods:
Roller compactor experiments were run with several raw materials while varying the roller compaction force, flow rate, and rotor speed. The process repeatability was characterized with in-situ FBRM® technology and offline analysis.
Ref: Singh et al, 2009
Ref: Chi-wan Chen, 2006
Results:
The influence of changing roller compaction force, flow rate, and rotor speed were quantified using real time in-situ FBRM® particle characterization. Compaction force and flow rate have a significant influence on the downstream particle distribution. Rotor speed had less effect on the particle distribution. A good correlation was obtained between the in-situ FBRM® and downstream process efficiency and product quality.
Ref: Lepore.J, Spavins.J, J Pharm Innov (2008) 3:79-87
Conclusion:
Roller compaction is a complex process with competing mechanisms of breakage and agglomeration. Using in-situ PAT for particle characterization, it is possible to quantify the effect of critical process parameters such as roller compaction force and flow rate. By characterizing these effects one can use FBRM® to optimize and control scale up process parameters to maintain compression consistency and product performance. (Burke et al., 2010)
Bibliography Reference
Verma, S., Lan, Y., Gokhale, R.,& Burgess J Diane (30 July,2009), "Quality by design approach to understand the process of nanosuspension preparation", International Journal of Pharmaceutics , vol. 377, no. 1-2, pp. 185-198.
Maltesen, M.J., Bjerregaard, S., Hovgaard, L., Havelund, S & De Weert, M.V. (2008), "Quality by design - Spray drying of insulin intended for inhalation. ", European journal of pharmaceutics and biopharmaceutics , vol. 70, no. 3, pp. 828-838.
Huang, J., Goolcharran, C. & Ghosh, K. (Dec 17, 2010), "A Quality by Design approach to investigate tablet dissolution shift upon accelerated stability by multivariate methods" European journal of pharmaceutics and biopharmaceutics, vol., no. pp.
Smith, T.J., Sackett, G., Sheskey, P. & Liu, L (2009), "Development, Scale-up, and Optimization of Process Parameters: Roller Compaction ", Developing Solid Oral Dosage Forms, vol., no. pp. 715-724.
Pitt, K. (November, 2009), "Roller compaction", Royal Pharmaceutical Society of Great Britain Tabletting Technology, vol., no. pp.
Kleinebudde, P. (2004), "Roll compaction/dry granulation: pharmaceutical applications", European Journal of Pharmaceutics and Biopharmaceutics, vol. 58, no. pp. 317-326.
Krycer, I., Pope, D.G. & Hersey, J.A. (February, 1983), "An evaluation of tablet binding agents part II. Pressure binders ", Powder Technology, vol. 34, no. 1, pp. 53-56.
Teng, Y., Qiu, Z. & Wen, H. (2009), "Systematical approach of formulation and process development using roller compaction", European Journal of Pharmaceutics and Biopharmaceutics, vol. 73, no. pp. 219-229.
Mansa, R., Bridson, R., Greenwood, R., Seville, J.,& Barker,H (2008), "Using Intelligent Software to Predict The Effects of Formulation And Processing Parameters on Roller Compaction", Powder Technology, vol. 181, no. pp. 217-22
Basu, P. (2009), "A Quality by design Approach to the understanding and predicting excipient properties and functionalities." The national institute for pharmaceutical technology and education. vol., no. pp. 1- 65.
Burke, G., Pandey, A., O'Grady, D., Dycus, B. & Smith, B. (2010), Roller Compaction Processes Optimization using FBRM® In-Situ Particle Characterization. Available from: Patheon Pharmaceuticals Inc. & Mettler Toledo, Web site: http://blog.autochem.mt.com/2010/02/roller-compaction-process-optimization-fbrm-at-line-particle-characterization-mettler-toled/ [Accessed: February 2, 2011].
