Application of Lower Magnetic Stirrer in Pharmaceutical Equipment

Application of Lower Magnetic Stirrer in Pharmaceutical Equipment

Mixer, as one of the most commonly used moving equipment, widely used in the chemical, food, dyes, cosmetics, pharmaceutical industry - the system has a dedicated space to its elaborate drug equipment guidance documents and standards ASME BPE file inside . Currently, under magnetic stirring device is becoming a popular trend in the biopharmaceutical industry.

Agitator is liquid, gaseous media mass forced convection and uniformly mixing device. As early as the industrial revolution before, people are already using a variety of each mixer-like. After the Industrial Revolution, stir stirrer used more and more diverse, professional technology, and now the mixer application and know knowledge is produced in the past, the practice of life continue to accumulate on the foundation and perfect.

Agitator type, size and speed of the stirring power in turbulent flow and overall pulse affects both the distribution between movable. In general , the power allocation for a turbine stirrer turbulent fluctuations Advantageously, the propeller mixer of favorable bulk flow. For the same type of agitator, the power consumption in the same conditions, the large-diameter, low-speed stirring mixing, power consumption is mainly in the bulk flow, facilitate macro-mixing. Small diameter, high rotation speed of the stirrer, the power consumption in the main turbulent flow pulsation, beneficial micro-mixing.

As biopharmaceuticals put forward higher requirements for the sterility and risk control of the agitator shaft seal , industrial magnetic agitators came into being in Sweden in the 1980s. Now in, under magnetic stirrer become the main market of the stream, and continue towards simplicity, high torque, large shear or very low shear, bearing materials safe, easy to clean online, online sterilization direction. For example , a lower magnetic stirrer dedicated to bioreactors , a lower magnetic stirrer for high-shear homogenization, etc. Whether it can prove that the agitator can be cleaned and sterilized online, and the bearing material safety has become the gold standard before the selection of biopharmaceutical agitators.

Working principle a magnetic stirrer desktop is to use a magnetic substance Laid sex repulsion resistance, by changing the base ends of the polar rotation to drive a magnetic stir bar; disadvantage of low energy conversion efficiency, is only suitable corpuscle volume of liquid was stirred .

The working principle of the industrial magnetic stirrer is: the inner and outer magnets are separated by an isolating sleeve in the middle , and the inner and outer magnets are driven by the motor to produce a magnetic coupling to achieve the purpose of transmission. Application of most pumps, magnetic pump can be up to no leakage, and the energy conversion most efficiently. And under the corresponding magnetic stirrer it is on a magnetic stirrer, due to the still not completed a full removal of the risks caused by seal, application areas domain very limited.

Since mixing is an experimental science, the amplification of the agitator is a complicated problem related to the technological process . So far, it can only be amplified through step-by-step experience, and based on the obtained amplification basis, it can be extrapolated to an industrial scale. Currently under magnetic stirring stirrer enlarged rely mainly on manufacturing companies in the usual mode of the buffer solution as the main simulation test, and on this basis to make a given type and amplification, are all custom-labeled improved model based on quasi- , Such as material customization, power customization, blade shape customization, and so on. Correct selection, choose the right mix stirrer to be placed in front of the user of a problem that must be addressed.

Desktop magnetic stirrer and a magnetic bar has been widely used, but only limited research development, small-scale level, people tend to generate a magnetic stirrer illusion that the magnetic stirrer is weak, low power, it can not be used for large volume and dead ends, clean-line cleaning (CIP) and sterilization-line (SIP), etc., however, this view already in reality should be overturned by the. Currently, under magnetic stirring it can already be suitable for maximum water 40t stir stirred, and even more, nor the type of application often more. From a structural point of view, typically with magnetic stirrer with a female bearing head; male shaft bearing, soldering tank bottom plate, the motor components. Horse up in advance with a drive permanent magnet pieces (not cyclic), turned in a position corresponding to the phase has the same number of permanent magnets, the polarity of each other just interesting, when installed after the motor drive head and the rotor in the permanent between the magnet mutual magnetic force coupling, motor operated drive head, a magnetic drive rotor operation, both the tank bottom is completely full separated, there is no mechanical drive shaft through the tank body.

The rotor design, the rotor and the bearing adapter, the gap between the rotor and the linear bearing contact relation to the effect of CIP / SIP, typically turn the head open as possible. Rotor material is 316L stainless steel, encapsulated permanent magnet bearing material most commonly used is silicon carbide ceramic, complete Inert for pH1 ~ 14, thermal expansion, in the case of water lubricated, can tolerate up to 5000 ~ 6 000 rpm speed not wear loss, since the operating state of the magnetic stirring device, is completely immersed in solution, the lubricating groove present in the solution can pass, so that the entire frictional interface is always covered with a water film, in rotation, friction is very small, not the particles can now be detected, for the final product does not pose a threat.

Often installed in the tank bottom portion inclined bottom, according to the manufacturer's installation guide feed line assembly, and the position of manhole / hand hole facing the bottom of the tank, to avoid the installation position of the tank bottom valve, the reason for this design may be a vortex and turbulence, so as to achieve a better mixing effect results, experiments have been made experts in this area, there are specific parameters for reference, of course, also the aspect ratio and the tank, the solution properties, viscosity, speed of stirring, the stirrer The matching and other factors are related.

Top of the tank installed with mechanical stirring stirrer compared, under magnetic stirrer advantage is clear:

●  Bottom stirrer-can stir to low liquid level volume! Especially suitable for high value-added sterile products;

●  No mechanical seal-no risk of cross-contamination and leakage of lubricating oil;

●  No baffle is needed-mixing is more efficient, and online cleaning is more effective;

●  Only need a spray ball, efficient CIP and SIP, easy to verify;

●The  overall purchase and maintenance cost is low;

●  Easy to maintain.

As the international bio-pharmaceutical giants continue in China, and these multinationals and foreign tanks to Chinese production, will also be their standard production technology and equipment abroad quasi intact copy to the country, so we are able to get a glimpse, for example, Sanofi-Aventis , GlaxoSmithKline, Novo Nordisk, Boehringer Ingelheim, Merial, etc., we suddenly discovered that the original biopharmaceutical giants have already used the lower magnetic stirring installed on the inclined bottom of the tank on a large scale. The most famous brand is the NovAseptic brand under Millipore, and its application is more common. It is the magnetic force on a sterile design and functional division stirrer, very representative, can be said that the trip flag industry. The structure design of the magnetic stirrer under NovAseptic and the operation of CIP/ SIP are briefly analyzed below. From the point of view use, under magnetic stirring devices are often used in certain biopharmaceutical off process key step, the speed and the shear magnitude of the force point of view:

1. The low-speed, low shear GMP type magnetic force stirrer (50 ~ 490 rpm), containing a protein, peptide and other biological macromolecules, liquid-liquid suspension composition mixed cells, easy to dissolve insoluble solids, readily miscible liquid -liquid mixing, heat transfer, especially for the blood liquid products, proteins, polypeptides, suspended animal cells sensitive to shear forces, or uniformity of mixing of the suspension before filling the final product;

2. The speed, moderate shear type USM magnetic stirrer (350 ~ 1 800 rpm): used in media preparation, no protein / polypeptide sterile formulation based component / injection mixing, a large volume of sterile liquid mixing, no bulk preparation of bacteria buffer, soluble solids bulky dissolution body;

3. The high-speed, high-shear type HS magnetic force stirrer (350 ~ 5 200 rpm): used to emulsify the oil and water, shear Insoluble solid cut dispersed, dissolved oxygen increases the amount of liquid and the like. Further, in high speed, high shear stirring magnetic base on the device, the deformation out of the line type HSI a high speed stirrer, and a can body can be into a self-loop structure.

They may be used in accordance with application purposes, used alone or in combination may be used. For specific applications, you can not be with a magnetic stirrer combined to obtain obtain the desired effect. For example, using the HS stirring an emulsion is formed of high shear, while the break with a vortex stirrer GMP, can create additional agitation and balance in the body. Can pass through this way to obtain a combination of different effective results, e.g. swirl control to prevent the foam produced raw increased agitation and the like.

High shear male magnetic stirrer with a shearing edge on the bearing stator or inner rotor is an outer edge or cut mover, turned, the male shaft upper bearing plate and the welding material is completely liquid contact . When the rotor/mover is running, the solid particles or liquid droplets are accelerated by the mover, collide violently with the stator , and are decelerated, then accelerated and collide again; or there is a violent collision between the particles and the particles , thereby causing the particles to be The size becomes smaller and smashed to form a uniform small particle size.

View from a suitable volume of a stirred, dried over design optimization of a magnetic stirrer, can stir the liquid from <1L ~ 40 000 L of just good biopharmaceutical unconventional stirred desired mix size, suitable viscosity 1 ~ 800cp, tolerance The temperature ranges from 0 to 200°C. Through the above magnetic stirrer of energy analysis is simple, use, easy to see, a magnetic stirrer have become biopharmaceutical trends of the industry, because it is the operation reduces the cleaning validation hemp lot of trouble, as far as possible at the same time magnetic stirrer performance of play to the extreme, which many professional design concept inseparable, promote bio common pharmaceutical and stirrer into two sectors step.

In the pharmaceutical and biopharmaceutical industries, the reference and the key parameters of interest include: a cleanliness, whether CIP / SIP; pollution risk; integrity of the tank; particulate matter produced the performance of students / bearing. The primary requirement of the bearing is an inert, broad chemical compatibility, no heavily genus residue, a low coefficient of thermal expansion; with medium compatibility; stirring performance, to the PQ; serving service and maintenance; reliability and durability; Process Design Flexibility easy to disassemble, in equal proportions amplification.

A magnetic stirrer under stirring effect by the following factors: the nature of the medium, the nature and the solution was stirred purpose, the fluid force learning - the shape of the tank, the liquid height / diameter ratio, the installation portion of the stirrer, with a tank Different liquid heights, the shape and speed of the stirring rotor , the technology of the application point of the stirrer, the budget, and the type of the magnetic stirrer.

Welding floor was once around the domestic difficulties of manufacturing enterprises, need welding segments, the need to control each segment welding temperature welding is safe key installed. Gradually subdivide the segments to 16 equal parts.

Rotor, bearings and motors installation / dismantle unloading sequence, and is installed under magnetic stirrer use of particular note of the link, it will directly affect the life of the agitator.

For example, a low-speed magnetic stirrer CIP : open tank bottom valve opens → 360 ° spray cream ball drainage washing → stirrer was turned on, rotation speed of about 100 rpm, min each about 10, . 4 ~. 5 times to the specific methodologies and repetition The number of times needs to be determined by verification tests according to the nature and viscosity of the material and liquid . If the spray ball only when the upper portion of the tank can be cleaned, does not need to be drained, a magnetic stirrer, immersion cleaning required, then drained, repeated several times, may follow cycloalkyl spray rinsing for some time, drained, distilled water was sprayed repeated Just wash it a few times.

SIP method in a magnetic stirrer: tank within distilled water drained off the tank and the tank bottom valve other outlet of the high pressure steam switch → open → 121 ~ 130 ℃, 0.5 h to.

Off-line cleaning method: using a special tool hook the head, unscrew the male bearing cleaning.

First need a clear good agitation standard standards, in order to establish the evaluation system stirring effect, there is no vortex can not stir as the quality standards, the level is stable or calm can not represent a good mix mix, according to need physical and chemical solutions nature, decide which way to detect most representative nature, most intuitive and accurate.

Stirring is a continuous process. The uniformity of the stirring is related to the stirring time, the properties of the solution (viscosity, concentration, density, etc.), the rotating speed of the stirrer, the height-to-diameter ratio of the tank, the shape of the tank and other factors. After a tank is shaped , by adjusting the speed, the stirring time, stirring volume, viscosity of the solution and changes in the nature of several ways of formula stirring to achieve optimal results.

In order to detect the degree of uniformity, according to the physical and chemical properties of the solution , samples can be taken at different time points of the stirring process to quickly detect the tested items and compare the values at different time points to obtain information about whether the stirring is uniform:

1 Ionic strength/conductivity. By stirring several time points during the sterile sampling, the time period before and after the detection of whether the conductivity of the same solution, stirred to determine the uniformity of the mix;

2 pH detection. Detecting whether the pH value before and after a certain period of time the solution was stirred for an actuator, in order to determine the uniformity of agitation, such as a vaccine adjuvant commonly used in Al (OH) 3, in suspension because of the different degrees to bring the pH of uniformly distributed The difference;

3 Marker concentration. Commonly used excipients such as a vaccine - human serum albumin by protein electrophoresis, ELISA assay before and the OD value or stirring or stirred if Stir the process;

4 Biological activity. Detect the stirred solution, take samples at several time points during the stirring process, and compare the characteristic indicators of the biological product solution, such as the titer of the virus vaccine , the characteristic enzyme activity of the live vaccine, etc.;

5 Detect the temperature before and after mixing, a tank suitable for heat transfer;

6 The density is tested with a densitometer;

7 Experiment was stirred ball density, you can see in real time the entire swirl flow, a variety of density distribution at different rotational speeds of the ball in the tank;

8 Brix meter;

9 standardized pattern formation was stirred stirring experiment, establishing a series of extreme stirred data, stirred and then non-extreme environments computer simulation, thereby judge off agitation effect.