Good manufacturing practice

Special equipment
The use of vitamins in a premix plant requires equipment which is chosen based on the specific constraints associated with vitamins: stability, flowability, Mixability™, and amount used.

Particular attention should thus be paid to the definition of the equipment for:

• Storage.
  
  
• Metering.
  
  
• Mixing.

Premix plant

Storage in bins
Vitamin storage bins should have the following characteristics:

• Smooth-walled stainless steel.
  
  
• Direct filling with dust removal system.
  
  
• Smallest possible cross-section, in order to reduce the surface of product in contact with the air.
  
  
• Angle of cone greater than the angle of repose.

The Danger of Dust
Any unit which handles, stores or processes products in powder form must respect strict design and manufacturing standards to protect against the emission of dust, and in particular against the explosion of dust.

Means of Prevention

• For presence of dust: It is necessary to avoid the formation of clouds of dust (Anneau de Pouyès at the filling shift) and to remove the deposits of dust which may accumulate (regular cleaning of the installations).
  
  
• Concerning the potential ignition sources: All electrical equipment and connections must be watertight; all the metal parts must be connected and properly grounded; the risk of any electrostatic discharge must be carefully assessed; maintenance work causing flames or sparks must be procedurally regulated.

Means of Protection

• Small equipment will be calculated to resist explosive pressure; Larger equipment is generally protected by discharging or venting; it is possible to inject an extinguishing product into an enclosure where a rise in pressure has been detected.

Regulation

• New European directives ATEX (Explosive Atmosphère) are applicable as from July 1st, 2003

The first directive (94/9/CE) provides health and safety requirements for electrical and non-electrical equipment intended for use in potentially explosive environments.
The second directive (99/92/CE) provides minimum requirements for improving the safety and health protection of workers potentially at risk from explosions.

The potential risk of explosion for powders is measured according to several criteria and allow for all appropriate precautions regarding each product.

MIE: the minimum ignition energy is the lowest energy value required to ignite dust/air mixture at atmospheric pressure and room temperature (mjoules):
< 3mj = high sensitivity
3mj < Emi < 10mj = sensitive
> 10 mj = low sensitivity

The maximum explosion pressure (Pmax -bar) and the KST value (bar m/s) describe the explosion behaviour of a combustible dust in a closed system.
The KST is used to calculate the maximum rate of pressure rise. The following dust explosion classes are assigned to Kst values.
ST0 = no explosion
ST1 = KST > 0 - 200 bar.m/s
ST2 = 200 < KST < 300 bar.m/s
ST3 = > 300 bar.m/s

Example
The following tests were made on a particle size lower than 100μm

Discharge and metering
The flowability and the amounts of products to be measured determine the choice of discharge and metering systems.

• Discharge
  
  Depending on the compressibility, simple metering equipment or combination with a complementary extractor is used.
  Standard metering equipment (screw-auger) is sufficient for the products which do not have a tendency to bridge (Image 1). For other products, it is recommended to use either an extractor Mass-Flow type (Image 2), or an extractor with vibrating bottom devaulter (Image 3).

Image 1	Image 2	Image 3

• Metering.
  
  In order to obtain a precise dosage, the metering system varies according to the amounts to be measured out. It is thus necessary to have several scales available on the same metering line.

Automatic weighing systems cannot always perform within the desired precision constraints. In these cases, it is recommended to manually weigh or predilute.

Mixing
Types of mixers
A mixer intended for preparation of vitamin premix products must be able to provide homogeneous mixtures of physically diverse particles incorporated at various inclusion levels in the mix.
A mixer should permit a homogeneous mixture of micro-ingredients with incorporation rates of 100 mg/kg to as low as 10 mg/kg. (Strauch -Bull. IFF N°273)

Specifications for a vitamin mixer

• Affords good homogeneity with the component included at the lowest possible content.
  
• Affords good homogeneity with components of different particle size.
  
• Short mixing duration.
  
• Variable degree of filling, with no loss of mixing efficiency.
  
• Complete emptying.
  
• Easy cleaning.
  
• Possibility of adding liquids.
  
• Ability to disintegrate clumps.
  
• Absence of heating during mixing.
  
• Low consumption of energy when starting and during mixing.
  
• Low maintenance costs.
  
• Reasonable purchase price.

Among these criteria, a certain number will have to be prioritized or compromised in order to achieve the best possible balance of performance with price.

Mixers are classified according to the intensity of the shear effect which they exert on the products to be mixed.

The following are thus discussed:

• Low-shear mixers.
  
  
• Mixers working by fluidization.
  
  
• High-shear mixers.

The characteristics of these mixers are presented below.

Low-shear mixers

• Rotating mixers: V-blender or Y-blender and cubic containers turning on an axle.
  
  
• Ribbon mixers, with a double spiral on the same axle, or with a single spiral in two tanks.
  
  
• Turning-screw vertical cone mixers.

These mixers are available in all sizes: liter-sized for the V-blender, several tens of m³ for the turning-screw vertical cone mixers.

They can be used for mixing vitamins (especially premixes), but may not cover all needs. They require the use of pre-screened materials.

These machines are also available in pharmacy, stainless-steel and integral-emptying versions.

Mixers working by fluidization:

• Twin-axle paddle mixers.

These machines, relatively new to the market, perform well for preparing vitamin mixtures.

These machines exist in mild stainless steel, with capacities ranging from 6 liters to 8,000 liters. They are all equipped with opening bases.

Pneumatic mixers with air-flow mixing are conventionally included in this category. This equipment is only used by the animal feed industries for mixing very fragile refatted powders which require working with cold air.

High-shear mixers

There are three types of high-shear mixers:

• Cylindrical plough mixer.
  
  
• Low-propeller mixers.
  
  
• Mixers with Z-shaped arms.

These mixers require higher power than those of the previous categories. They may also have a blending function.

These mixers are often employed for mixing vitamins, since they perform well and are adequate for a wide range of formulations.

Their finish, which is generally stainless steel, ensures easy emptying and cleaning. However, these machines create violent air movements in the plant, and thus require highly-Ieaktight peripheral equipment.

Mixing procedures
Prior precautions

• Ensure that the equipment is well suited to the type of product to be mixed.
  
  
• Make sure that static parts and mobile parts of the mixer are fully grounded with the rest of the equipment.
  
  
• Verify that the amount to be mixed is in accordance with the mixer specifications (insufficient or excess filling will make it impossible to perform correct mixing).

Sequence of charging the mixer
Correct mixing is started at initial charging of the mixer. Loading should, ideally, be performed in three steps:

• First step
  Plant carrier: load a fluid, neutral component of fairly low apparent density.
  
  
• Second step
  Powders and beadlets: load these components while making sure that none of them stagnate in a calm zone of the mixer. The loading order must take into account the mutual affinities of the products. Avoid loading electrostatic and / or sticky components either concurrently or sequentially; instead alternate with components of a more neutral behavior.
  
  
• Third step
  Inorganic diluent: complete the loading with the densest component of the formulation.

Use of a liquid for improving premix quality
A mixture of particularly dusty or "flushing" components may pose handling problems by workers or in automatic metering machines. These problems are solved by the addition of a liquid binder.

The liquids usually used are antioxidant-treated or neutral oils or fats of low viscosity. They are added to the carrier, at a rate of 1 to 4 %, before incorporation of the powdered vitamin products. In certain cases, vitamin E oil, or a E oil 75% (less viscous preparation), may also be used.

The addition is performed by flat-jet nozzles which ensure a quality injection: precise impact onto the mixture, fine and calibrated drops without creation of fog above the mixture.
The liquid should impact the mixture in a dynamic mixing zone where the product is in regular movement.

Several liquids should be avoided, since they are liable to affect the stability of the vitamins in premixes:

• Liquid choline chloride: its aqueous composition and the free ions make it a very aggressive liquid with respect to all vitamins in the premix - in particular vitamins K₃, B₁, B₆ and folic acid.
  
  
• The hydroxy analog of methionine: an acidic liquid which attacks the majority of vitamins, including vitamins A, D₃, E and K₃ as well as calcium pantothenate and folic acid.
  
  
• Sodium methioninate: high moisture content, alkaline, and more particularly aggressive with respect to vitamins E, B₁, B₂, B₆ and C.
  
  
• Acidic oils or fats which possess free radicals, catalysts of all redox reactions. These products may reduce the vitamin activity of the premix.