Transfer of Technology (Part I)

Robustness

is the ability of a process to demonstrate acceptable quality and performance, while tolerating variability in inputs.

Robustness

It is a function of formulation and process design

Robustness

can be determined via proactive process monitoring.

Technology transfer

is the process by which the manufacturing process and analytical method are transferred from one manufacturing unit to another unit or from Research and Development (R&D) to manufacturing unit.

Process Technologist

Central focus for transfer activities

Process Technologist

Collates documentation from donor site

Process Technologist

Performs initial assessment of transferred project for Feasibility, Compatibility with site capabilities and Establishes resource requirements.

Quality Assurance (QA) Representative

Reviews documentation to determine compliance with marketing authorization (MA).

Quality Assurance (QA) Representative

Reviews analytical methods with QC to determine capability, equipment training requirements.

Quality Assurance (QA) Representative

Initiates conversion of donor site documentation into local systems or format.

Quality Assurance (QA) Representative

Initiates or confirms regulatory requirements, e.g., change to manufacturing license; variations to MA if process changes needed, etc.

Production Representative

Reviews process instructions (with process technologist) to confirm capacity and capability.

Production Representative

Considers any safety implications, e.g., solvents; toxic; sanitizing materials.

Production Representative

Considers impact on local standard operating procedures (SOPs).

Production Representative

Considers training requirements of supervisors or operators.

Engineering Representative

Reviews (with production representative) equipment requirement.

Engineering Representative

initiates required engineering modifications, change or part purchase.

Engineering Representative

Reviews preventative maintenance and calibration impact, e.g., use of more aggressive ingredients; more temperature sensitive process, and modifies accordingly.

Quality Control (QC) Representative

Reviews analytical requirement.

Quality Control (QC) Representative

Availability with instruments.

Quality Control (QC) Representative

Responsible for analytical method transfer for drug substance and drug product.

Mixing

is defined a process that tends to result in a randomization of dissimilar particles within a system.

Newtonian

have a constant viscosity that doesn’t change, no matter the pressure being applied to the fluid.

Non-Newtonian

the opposite of Newtonian; if enough force is applied to these fluids, their viscosity will change.

Dilatants

get thicker when force is applied

Pseudoplastics

get thinner under the same circumstances.

Rheopectic

is very similar to dilatant in that when shear is applied, viscosity increases.

Rheopectic

viscosity increase is time-dependent

Thixotropic

decrease in viscosity when shear is applied

Thixotrophic & Rheopectic

a time dependent property

Gypsum paste

Cream

Examples of Rheopectic

Paint

Cosmetics

Glue

Examples of Thixotropic

Bulk Transport

The movement of a relatively large portion of the material being mixed from one location in the system to another.

Bulk Transport

This is a simple circulation of material in a mixer but does not necessarily result in efficient mixing.

Bulk Transport

For it to be effective, rearrangement or permutations of various portions of the material should be done.

Bulk Transport

It is usually accomplished by the means of paddles, revolving blades or other devices within the mixer arranged so as to move adjacent volumes of the fluid in different directions.

Turbulent Mixing

a direct result of turbulent fluid flow, which is characterized by random fluctuation of the fluid velocity at any given point within the system

Turbulent Mixing

Highly effective, mixing is due to turbulent flow which results in random fluctuation of the fluid velocity at any given point within the system

Laminar Mixing

is frequently encountered when highly viscous fluids are being processed.

Laminar Mixing

Mixing of two dissimilar liquids through laminar flow, i.e., applied shear stretches the interface between them.

Laminar Mixing

Suitable for liquids which require moderate mixing.

Molecular Diffusion

The primary mechanism responsible for mixing at the molecular level is diffusion resulting from the thermal motion of molecules.

Molecular Diffusion

When it occurs in conjunction with laminar flow, it tends to reduce the sharp discontinuities at the interfaces between the fluid layers, and if allowed to proceed for sufficient time, results in complete mixing

Molecular Diffusion

This process can be described quantitatively in terms of Fick’s first law of diffusion.

Scale and integrity of segregation

The quality of mixtures must ultimately be judged upon the basis of some measure of the random distribution of their components.

Scale and integrity of segregation

Such an evaluation depends on the selection of a quantitative method of expressing the quality of randomness or "goodness of mixing ".

Batch mixing

when the material is to be mixed is limited in volume to that which may be conveniently contained in a suitable mixer, this is not usually feasible.

Impellers

The distinction between its types is often made based on type of flow pattern they produce, or on the basis of the shape and pitch of the blades.

radial, axial, and tangential

Three basic types of flow may be produced by Impellers:

Propellers

characteristically produce flow parallel to their axes of rotation whereas turbines may produce either axial or tangential flow, or a combination of these.

Propellers

It consists of number of blades, generally 3 bladed design is most common for liquids.

Propellers

Blades may be right or left-handed depending upon the slant of their blades

Propellers

Used when high mixing capacity is required

Propellers

Effective for liquids which have maximum viscosity of 2.0pascals.sec or slurry up to 10% solids of fine mesh size.

Propellers

Effective gas-liquid dispersion is possible at laboratory scale.

Propellers

are not normally effective with liquids of viscosity greater than 5pascal.second, such as glycerin, castor oil, etc.

Turbines

consists of a circular disc to which several short blades are attached, blades may be straight or curved.

Turbines

The diameter of the turbine ranges from 30-50% of the diameter of the vessel.

Turbines

rotate at a lower speed than the propellers (50-200rpm).

Turbines

give greater shearing forces than propellers through the pumping rate is less.

Turbines

suitable for emulsification.

Turbines

Effective for high viscous solutions with a wide range of viscosities up to 7.0 Pascal. Second.

Turbines

In low viscous materials of large volumes this create strong currents which spread throughout the tank destroying stagnant pockets.

Turbines

They can handle slurries with 60% solids.

Turbines

are suitable for liquids of large volume and high viscosity, if the tank is baffled.

Paddles

Consists of a central hub with long flat blades attached to it vertically.

Paddles

Sometimes the blades are pitched and may be dished or hemispherical in shape and have a large surface area in relation to the tank in which they are used.

Paddles

rotate at a low speed of 100rpm.

Paddles

Two blades or four blades are common.

Paddles

are used in the manufacture of antacid suspensions, agar and pectin related purgatives, antidiarrheal mixtures such as bismuth-kaolin

Vortex formation

is not possible with paddle impellers because of low-speed mixing.

Paddles

Mixing of the suspension is poor therefore baffled tanks are required.

Airjets

Subsurface jets of air, or less commonly of some other gas, are effective mixing devices for certain liquids.

Airjets

are usually arranged so that the buoyancy of the bubbles lifts liquid from the bottom to the top of the mixing vessel. This is often accomplished with the aid of draft tubes.

Airjets

The overall circulation in the mixing vessel brings fluid from all parts of the tank to the region of itself

Fluidjets

When liquids are to be pumped into a tank for mixing, the power required for pumping often can be used to accomplish the mixing operation, either partially or completely

Fluidjets

the fluids are pumped through nozzles arranged to permit good circulation of material throughout the tank.

Fluid jets

behave somewhat like propellers in that they generate turbulent flow in the direction of their axes.

Fluid jets

They do not in themselves, however, generate tangential flow, as do propellers.

Baffles

Bulk transport is important in mixing and is particularly desirable in the initial stages, when segregation may be present on a large scale.

Baffles

placement depends on the type of agitator used.

Continuous Mixing

produces an uninterrupted supply of freshly mixed material and is often desirable when very large volumes of material are to be handled.

Baffles

For bulk fluid flow to be most effective, an intermingling must occur between materials from remote regions in the mixer. To accomplish this, it is necessary to install auxiliary devices for directing the flow.

In a tube/pipe which the material flows and in which there is very little backflow or recirculation

In a chamber which the material flows and in which there is very little backflow or recirculation

Continuous mixing can be accomplished in two ways:

Mixer Selection

The first and most important consideration in any mixing problem is equipment selection.

Mixer Selection

Economic considerations regarding processing, e.g., time required for mixing and the power expenditure.

Mixer Selection

Cost of equipment and maintenance

Mixer Selection

The physical properties of the materials to be mixed, such as density, viscosity, and miscibility.

Monophase Systems

The viscous character and density of the fluid(s) to be mixed determine to a large extent the type of flow that can be produced and also, therefore, the nature of the mixing mechanisms involved.

Monophase Systems

Fluids of relatively low viscosity are best mixed by methods that generate a high degree of turbulence (air jets, fluid jets, and the various high-speed impellers).

Monophase Systems

A viscosity of approximately 10 poise may be considered as a practical upper limit for the application of these devices.

Monophase Systems

Thick creams, ointments, and pastes are of such high viscosity that it is difficult if not impossible to generate turbulence within their bulk and laminar mixing, and molecular diffusion must be relied upon.

Monophase Systems

Mixing of such fluids may be done with a turbine of flat blade design

Monophase Systems

A characteristic feature of such impellers is the relative insensitivity of their power consumption to density and/or viscosity.

Polyphase Systems

The mixing of systems composed of several liquid or solid phases primarily involves the subdivision or deaggregation of one or more of the phases present.

Polyphase Systems

When mixing of two immiscible liquids:

Then distributed throughout the bulk of the fluid

One phase should be subdivided into globules

Polyphase Systems

The process usually occurs by stages during which the large globules are successively broken down into smaller ones

Polyphase Systems

Two primary forces come into play here: the interfacial tension of the globules in the surrounding liquid, and forces of shear within the fluid mass.

Polyphase Systems

The processes of homogenization, suspension formation, and emulsification may be considered forms of mixing.

Emulsions

may be prepared by using one of several mixers that are available.