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Blending - A unit operation

Instructed by : Dr. B. RoheraPresented by : Niketkumar B.Patel

X01801641

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Outline : Introduction Mechanism of mixing Scale up in mixing Segregation Powder blend uniformity Conventional approaches Thermal effusivity measurement NIR spectroscopy as a PAT initiative Laser induced fluorescence technique Summary

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Introduction : Blending/mixing is the most common operation that can be

observed in many industries like food, glass, paints, ceramic, fertilizers and pharmaceutical industry.

Blending indicates much smoother and inseparable mixing of the particles but both terms can be used interchangeably.

Mixing is “putting together one or more substances into one mass and ensuring their complete diffusion among each another.”

With respect to pharmaceutical industry mixing would be the “production of a blend whose sample reflects exactly, or at least

by pre-defined accuracy, the ratio of the added base materials. “

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Mixing :

Active substances + excipients↓

Mixing↓

Granulation↓

Compression↓

Packaging

Main goal of blending processes is tablet production which requires identical ingredients and homogenous distribution of the active pharmaceutical ingredient (API) as well as additives.

Problems in blending inhomogeneity in material blends deblending due to exceeded

blending times increased time and cost

consumption due to exceeded blending times

Pharmaceutical industry – solid blend of agent (API) and several additives (up to 10) are mixed together.

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Mechanisms of mixing :Convection : Involves transfer of groups of particles as a mass (mainly parallel to flow) Convective mixing occurs when circulation patterns are set up in a powder

mix. Motion imparted by impeller as in Ribbon Blender.

Diffusion : Redistribution of particles by random motion Vertical or axial motion as seen in rotational blenders.

Shear : It involves movement of particles within a group of relatively slow moving

particles. There is formation of slip planes in the mixture. Motion imparted by high shear mixers.

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Scale up : It involves scaling up the quantities of the materials after achieving process

parameters such as content uniformity, particle size and distribution, surface area and potency at a small scale.

Various parameters are to be determined at a small scale like mixing time, speed of mixing, volume of charged powder mix and energy imparted to mix.

During scale-up, it is essential to evaluate every possible effect that modifications to the mixer size may encounter.

Critical parameters for the given materials which would affect the process parameters most can be determined at the pilot scale only.

Drug deficiency has also been found to be a problem with scale-up due to the adsorption of drug to the wall of the mixer, which did not happen on the pilot scale.

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Several points to be followed during scale up process : Changes in the scale during scaling up should not change the dominant

mixing mechanism (eg convective to dispersive).

For free flowing materials, the number of revolution is more important rather than rotation rate.

For the cohesive materials, mixing depends on shear rates so rotational rate is more important.

Adding asymmetry to the mixer; either via design or via introduction of the baffles can largely affect the mixing process

In the case of upgrading the equipment or selection of new mixer- it leaves behind all the data of the materials for the old mixer invaluable.

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Segregation : Segregation is a main problem to be encountered with during mixing

process; also known as demixing.

Segregation refers to the separation of the coarse from fine material during the flow of a powder or the vibration of a bed of powder.

Segregation is a function of The powder itself physical and chemical properties size density charge

cohesion Forces induced on the particles…air flow vibration gravity Flow sequence…due to equipment

Overmixing- mixing after achievement of homogeneity of powder blend may also cause segregation.

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Continue..There is three types of segregation :

Size segregationDensity segregation

Trajectory segregation

Several approaches to minimize segregation :

Ordered mixing can minimize segregation. Granulation can be also carried out to prevent segregation. Changes in particulate characteristics of drug and excipients may

eliminate particle size differences or improve adhesion between a coarse diluent and fine particle drug.

Avoiding sloping surfaces in machinery will also help reduce segregation. BINSERT is the instrument which is used to minimize segregation.

Segregation is the property of material and equipment so it can be minimized; not prevented.

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Powder blend uniformity : Powder Blend Uniformity - refers to active ingredient distribution or

homogeneity in the “final” blend or mix.

Powder Blend is encapsulated, tabletted, or filled into single or multiple dosage units so in this case powder blend uniformity is important in deciding quality of end product.

“Adequacy of Mixing” - satisfactory blending step to assure uniformity and homogeneity is a term used by the US Food and Drug Administration (FDA) for powder blend uniformity.

Product non uniformity occurs due to Due to blend nonuniformity Due to segregation

Blend non uniformity occurs due to Due to poor blending Due to sampling errors

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Continue… The content uniformity of the tablets is an important quality measure of the

final product.

As the content uniformity is closely related to the uniformity of the blend, it is important to monitor blend uniformity.

Inhomogeneities of a blend can either be due to insufficient mixing or to deblending under transportation or storage of the blend.

Blend uniformity is a function of both the formulation and the mixing action.

Overmixing is also a reason for segregation which causes a blend uniformity.

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Blending non uniformity:Insufficient blending and overblending both cause severe problems as

discussed below. Insufficient blending results in the lack of content uniformity can lead to

product recall by the FDA for subpotency or super-potency reasons. Recalls for sub-potency represent the top reason for drug recalls in current days

If blending is excessive, then the particles will segregate (demix or deblend) on the basisof particle

size and mass which again lead to problems in content uniformity. In addition, temperature increases that occur during blending can damage

some of the sensitive components and eliminate the potential for continued blending to return the mixture to a homogenous state.

So determination of blending uniformity and blending end point is very important.

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FDA perspective :

According to CGMP CFR TITLE 21 PART 211 mainly 211.110 for sampling and testing of in process material and end products of subparts f state the proposed three criteria by FDA

Assay one sample per location , n ≥ 10 RSD for all individual results ≤ 5 % All individual RESULTS within 10.0% of mean

NIR spectroscopy is getting attention as ”real” time process control which also facilitates PAT initiation.

So sampling is the primary requirement for the assay.

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Sampling for an assay : The most commonly used method fro deciding blend uniformity is withdrawing

samples from the blend and carrying out assay using HPLC or UV.

In practice blend uniformity is assessed by collecting a number of samples from the blend, each sample being of the size of 1-3 times the corresponding tablets; which is a requirement.

The sampling locations must be carefully chosen to provide a representative cross-section of the granulation. The resulting samples are then assayed using the same methods used to analyze the finished product.

Content uniformity is established if the drug content of the samples conform to a predetermined criterion.

Currently sampling is done with sampling thief probe that is inserted into the powder mixture to withdraw the samples.

Thief probes make sampling possible from the bottom and middle portions of the mix also.

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Continue…

Groove thief End cup sampler

This device consist of an outer hollow sleeve with an opening running the length of the pipe (66 in.) which surrounds a rotating inner pipe. This inner pipe is solid except for a sampling cavity running the length of the pipe.

This sampler consists of a pair of thin rods, one has a cup mounted at the end, the other is attached to a rotating cap aligned with the top of the cup.

A major drawback of this sampler is that only a single sample can be acquired at a time.

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Problems with sampling thieves: Sampling with a thief probe is not a good method to carry on blending

homogeneity on it.

This method always keep a question in front “Is this poor blending or inaccurate sampling ??” responsible for blending in homogeneity.

The whole validated blending process is carried out on the basis of “nonvalidated” sampling method.

There is two golden rules for sampling : Sample should be taken from a moving stream of powder, and Sample the whole stream for equal periods of time, rather than from part of

the stream for all of the time

None of them can be fulfilled when we are using a thief probe for sampling.

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Continue… Thief probes often exhibit large uncertainty and error due to the disruption of

the powder bed by the probe while inserting it in a powder blend for sampling.

Another main concern is the uneven flow of different powder species into the probe during sampling.

Several times it is hard to push thief probe in the mix and application of force may break the particles.

While taking the thief probe out of the mix after sampling, surface material may contaminate the sample.

Not even a standard probe or specifications for that is available.

So sampling with thief probe is not trustworthy.

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Stream sampling Stream sampling is also an alternative to the

use of sample thieves. This report describes the implementation of stream sampling by capturing the blend in stainless steel cups as it flowed from the bottom of the blender.

This type of sampling follow the two golden rules of sampling.

More number of samples can be taken compare to sampling thief because there is no possibility of particle breakage during sampling.

Stream sampling is not able to target locations that are suspected of providing poor blending.

The goal of stream sampling is to obtain representative samples and not to target specific locations, which it actually does.

Schematic representation of stream sampling.

So none of the methods looks efficient for carrying out an assay.

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Carrying out an assay: Samples collected as indicated above are sent to UV spectroscopy and High pressure liquid chromatography for assay.

Assay for the active ingredients are carried out and all data is collected and various statistical approaches are used for the determining powder blend homogeneity.

Sometimes, to avoid repeataion of the sampling due to above discussed disadvantages three or four assays are carried out with the help of one sample.

They give off line measurement of the blend uniformity because sampling is the prerequisite to carry out the assay.

Most widely and well accepted current method for determination of blending uniformity is HPLC due to Precision, Reproducibility, Sensitivity and Solution Stability - Up to 24 hr.

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Assessment of blend uniformity :

Round represents the results from the left side samples

Square represents the result from the right side samples

Triangle represents the average potency

So as the potency of left side and right side samples approaches average potency ; blend uniformity is meant to be developed

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Problems with the assay methods: The limitations of these tests lie in their inherent analysis time as

well as the necessity of removing samples from the blender.

Errors occurs during the sampling or limitation of conventional sampling method limits the accuracy of this method

In this sense, blend homogeneity obviously addresses only the distribution, i.e. the content uniformity of the active drug substance while assuming that the excipients are also evenly distributed.

The role of the excipients,which not only improves dosage form

compliance, but also affects the technological and biopharmaceutical performance of the formulation, is simply neglected.

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Thermal effusivity measurment : Simple and advanced method which gives an idea about blend

homogeneity and blending end poit. It is nondestructive method of analysis. E f f u s i v i t y = k   ρ c p the thermal conductivity (k), heat capacity (cp), and density ( p ) of the

material.

So, powders would have different effusivity readings depending on their ability to transfer heat through and between their particles.

And the resultant powder blend has its unique thermal effusivity which all the powders ultimately going to achieve at the point of blending homogenity.

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Carrying out a determination : Eight individual powder components of a commercially available formulation

were evaluated for their effusivity measurement Each has a different effusivity…measured…range for the experiement is

determined Triplicate results have taken ….low standard deviation among results should

be obtaied

Figure : component effusivity; range of 180 to 600 is obtained.

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Continue..

Figure 3 shows the results of testing the second set of samples extracted at various times from a commercial blender. As shown for the previously described method, each point on the graph representsthe result of triplicate tests conducted on one aliquot from the vial trend in the average results is to increase and then level off.

The increase is suspected to result from improved packing, whichremoves air from the volume of material tested

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Continue…

Figure indicates the change in effusivity in the first 15 min of blending and shows the six individual results rather than the average.

As the blending increase ….concentration of individual components reduces….whereas blend concentration increase till the homogeniety achieved.

The first sample,drawn at 2 min, had a large scatter in the results because of the nonuniformity that existed at the beginning. As the blending time progressed toward 15 min, the repeatability improved as an indicator of the uniformity.

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Continue…

Relative standard deviation of effusivity of six samples are taken which approaches the minimum value which is achieved at the blending end point.

+ Relative standard deviation is minimum at end point for this

off line manner measurment

Figure indicates RSD as determination of blending endpoint

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Advantages Non-destructive process - does not alter excipients or other ingredients Eliminates thieving - does not compromise containment Retrofittable - can be incorporated on existing blending equipment Easy to clean and maintain Accurate results - strong correlation with HPLC and other methods Cost savings - reduces operating costs and lost revenue due to discarded

batches Reduced liability risk Improved batch traceability

EPS sensor package is the available instrument on this technology.

But this technique gives offline measurement which lacks it in PAT initiation compare to Near Infra red spectroscopy.

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Near infra red spectoscopy : Near Infrared Spectroscopy (NIRS) is a versatile analytical technique when

analyzing solids powders.

It is based on dipole moment changes and molecular vibration altransitions of molecules.

The absorptions in this region are due to overtones and combination bands of the fundamentals bands of the mid-IR molecular vibrational bands.

The radiation in the NIR can interact with matter in three different waysDiffuse Reflectance Transmission

NIR is the most promising method for determination of blend homogeneity and blending end point.

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Carrying out a determination : Ibuprofen and spray dried lactose are mixed and blending homogeneity is

determined.

Figure indicates NIRS diffuse reflectance spectra of ibuprofen (dashed lines) and lactose in the beginning of mixing.

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Continue…

Figure shows nir spectra at different time intervals indicating homogeneity is achieved at around 3 minutes.

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Continue…

Blending profile obtained from the entire spectral range ( ) and over the spectral range used in developing the calibration model

In each case the standard deviation of the spectra at each wavelength of the spectral range was first calculated. The average standard deviation over these wavelengths was then calculated and plotted versus blending time.

Figure indiacates standard deviation for determination of blending homogeneity.

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Understanding the NIR

Figure shows change in NIR absorbance of diluents as the blending process approaches

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NIR spectoscopy to instruments

The NIR spectrophotometer is configured with a fiber-optic probe, which is interfaced with the blending vessel at the point of rotation.

NIR Spectra are acquired in real-time and using appropriate data pre-processing and chemometric analysis, blend 'homogeneity' plots are derived.

Figure shows Schematic representation of NIR spectroscopy with blender.

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Instrument :

Blendalyser is the instrument available in the market providing NIR as an assay tool.

Mounted on the top of blender in rotating movement and having sensing probes at various places of the blender.

Continuous and accurate determination of blend homogeneity can be determined.

Blender system

BlendAlyser

Connection via 4“ standard flange using a flange

fastener

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NIR preference over other techniques : NIR works at the speed which can be less than one minute per

measurement.

Capability to measure samples at a single point or at multiple locations either inside or outside the blender

Companies, is a challenging approach intended to assist the progression of real-time or parametric release and quality-by-design concepts by providing an opportunity to move from the laboratory-based besting to document quality paradigm to a continuous quality assurance paradigm

NIR spectroscopy may be one of the major PAT tools, since these techniques are well-suited for at-line, in-line and on-line measurements.

FDA announced NIR spectoscopy as the PAT initiative and also prefers NIR results over the conventional results.

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Limitations of NIR :

The majority of overtone peaks observed in a NIR spectrum arise from the X-H stretching modes. They are between 10 and 1000 times weaker than the fundamental bands so NIR is usually a weak signal, except for water,

There is a limitation to the sensitivity of this method for high potency drug formulations where drug content may be below 1% wrw in the mixture.

The method requires require intense data pretreatment and chemometric data analysis for method development

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Laser induced fluorescence technique :

Laser-induced fluorescence (LIF).technique to monitor homogeneity of solid powder mixtures during component blending.

Figure shows schematic representation of the LIF techinques.

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Continue..

The sensor uses an argon laser as the excitation light source. The laser beam is directed into a fiber-optic cable connected to the

Photosensor Module containing the lens and the detector Photomultiplier tube.

Inside the photosensor module, a dichroic mirror reflects the laser beam at 90 degrees to the sample.

The fluorescent signal that is emitted from the sample is collimated by the lens and passes through the dichroic mirror and an emission filter the detector.

Signals are converted to voltage and recorded by which is interfaced to a computer

Reflected Light is prevented from reaching the detector by the dichroic mirror and the emission filter.

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Determination of blend uniformity :

Triamterene is the active pharmaceutical ingredient and Direct compaction anhydrous lactose are used in all experiments.

Changes in bulk density of the powders in the blender correspondedto a proportional change in LIF signals.

Figure shows effect of bulk densities on LIF signals.

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Continue…

Figure shows data acquisitions for lactose and triamteren in LIF signals.

As the number or rotations increasing there is decrease in LIF signals which become constant after a certain rotation which can be assumed as blending end point.

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Continue…

Figure indicates sensitivity of LIF to the location by indicating data from top and the bottom of the blender.

• When the API was loaded at the bottom, the initial signal was high due to close proximity of the LIF sensor near the bottom. • When loaded on top of the blender, the initial signal was low since the sensor was responding only to lactose during the first few rotations. • In both cases, the LIF signals reached an equilibrium state of blend homogeneity at the same value with signal deviations of less than 5%

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Online measurement :

NIR spectroscopy and LIF technology gived on line measurement for the blending homogeneity and blending end point.

There is a large (Factor of 10-15) reduction in cycle time of blending when online measurement are used because there is no need for sample collection, assay and data collection.

There is a large variability reduction in blend process development

time and process becomes more accurate and economical.

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Summary : As we have seen mixing is very important unit operation in

pharmaceutical manufacturing; in which determination of blending time and achieving blending uniformity is formost.

Conventional methods are having their own disadvantages which turns manufacturers to the expensive online determination techniques.

FDA’s PAT initiative, accuracy in the results and time saving will make these relatively expensive methods the choice of manufacturers in near future.

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Thank you…