Not a drop more, not a drop less

When filling aseptically, liquid must be filled into vials rapidly and precisely to achieve high production speeds. Ivan Ragazzini of IMA Life and Roberto Cazzaniga of Emerson Process Management Italia, explain how IMA’s Xtrema LV in-line filling and stoppering machine meets these criteria

The Xtrema LV recently developed with the aid of EPM’s Micro Motion mass flow meters

Working at the forefront of aseptic processing and filling technology, IMA Life technicians recently developed in-line filling and stoppering for the company’s Xtrema Large Volume (LV) machine. This machine enables the dosing of liquids in an aseptic environment with excellent results in terms of filling range, accuracy and repeatability – and with an output of up to 600 units per minute.

Key to the innovative solution is the Micro Motion mass flow meter supplied by Emerson Process Management, whose staff worked with the R&D department at IMA in a development process that lasted five years. Even though the Micro Motion flow meter is a standard catalogue product, the final result, the Xtrema LV machine, is an innovative customised solution.

Even though the Micro Motion flow meter is a standard catalogue product, the final result is an innovative customised solution

‘Innovation and customisation are the main competitive tools that allow IMA Life to deliver special machines,’ says Ivan Ragazzini, who is responsible for hardware and software at IMA Life. ‘Standard catalogue machines do not exist within IMA. We generally start from a customer question, such as how can I get an output of up to 600 bottles per minute with high level of accuracy and repeatability? Therefore, although we speak of the Xtrema LV family, the machine is always customised to the customer’s own needs.’

The machine is dedicated to aseptic filling and has the following tailored features: a wide filling range, from 50ml to 1 litre for large volume parenterals; high accuracy and repeatability; flexibility in batch changes and in Clean in Place and Sterilisation in Place (CIP and SIP) operations. All of this is independent of the type of product to be filled, the filling volume requirements and the product temperature or density. While relying on check-weighing technology, providing a double cross-check (tare input detection and output gross weight), the machine does not use any conventional pumps; instead No. 8 Micro Motion mass flow meters are installed upstream of the filling nozzles.

Changeover with one tool

It was an ergonomic problem that led the company to consider the flow mass measure. The use of 1 litre or 500ml syringes in a linear machine in an aseptic environment is not recommended because it would involve the set up of fractionated dosages, with consequent implications in terms of filling accuracy, and the risk of incorrect filling – not to mention the cost implications of the procedures that would have to be applied at every batch change. Rather than equipping each of the eight heads with three dosage syringes (from 50–150ml, 150–400ml and 400–600ml ), which would involve a total of 24 devices, the new Xtrema LV employs eight universal measuring instruments that do not need to be disassembled either at a batch change or for the cleaning and sanitising phases, regardless of the liquid to be filled, and whatever the fill volume within the range of 50–1,000ml.

It was an ergonomic problem that led the company to consider the flow mass measure

As an alternative to volumetric or peristaltic pumps, this solution meant that IMA’s engineers were able to get a very good accuracy – 0.5% to 3-Sigma on a production batch lasting eight hours. That means, for example, when filling a batch of 200 doses per minute for the entire work shift, the nonconformity of bottles would be around 10 units out of nearly 100,000 products. This high level of accuracy leads to two advantages: certainty of the dosage accuracy and repeatability in producing the largest number of vials possible within the tolerance range allowed by the regulations.

Quality criteria

The fast filling of products in an aseptic environment is a critical operation, not only with regard to the accuracy, but also with regard to strict quality parameters that customers require during production. For example, to get a very slight product splash on a vial’s external surface during filling would be a ‘non conformity’. This is the reason why valve control is not driven by flow meter directly, but by a logic developed by IMA.

The motion profiles that drive the dispensing valve’s opening and closing operations have been developed by IMA and are maintained by soft logic PLC. The mass meter system is then used as a pure measuring instrument, whose features in terms of accuracy and frequency allowed the development of specific dosing profiles that eliminate any dripping or product splash on the vial body – even at high speeds.

Micro Motion meters are the most reliable, flexible and robust solution for meeting various needs

The Micro Motion mass flow meters are based on a principle called the Coriolis force, named after the French physicist who studied it extensively in the first half of 1800s. The Coriolis force is proportional to the mass of a body in motion in a uniform circular motion. Using this principle the Micro Motion mass flow meters allow accurate measurements directly inline, that is to say, at the same time as the filling process. In addition to the mass flow rate measurement, the range of Micro Motion tools can also take measurements of volume, density, temperature and concentration, all integrated.

Independent of the fluid type (e.g. liquid, gas, sludge, etc.) being measured, the environment and/or the type of process, Micro Motion meters are the most reliable, flexible and robust solution for meeting various needs. As flange-type devices, they can be installed almost anywhere. Furthermore, once set, drift is absent, therefore the instrument does not require periodic calibration, as is the case with load cells, for example.

The ability to perform measurements directly in line dramatically improves operating times: the mass flow meter can run in a single cycle what previously would have had to be run in separated phases, thus increasing equipment productivity and availability.

Cleaning and sterilisation

The high mass flow flexibility allowed IMA Life to obtain other benefits, such as in cleaning and sanitising the equipment. Ensuring the perfect cleanliness from the product tank right through to the nozzle is no small matter. There are international standard procedures on the basis of which it is possible to determine whether washing prior to sterilisation, has been effective; in other words, to verify if the necessary quantity of cleaning solution has reached all internal surfaces to avoid cross-contamination between one batch and the next.

Current practices require the use of Riboflavin (vitamin B2) diluted in water. This substance must be introduced inside the circuit before being submitted to the CIP procedure. The substance acts as a marker indicating either that the washing cycle has been successful, or if there is any residual trace after the washing cycle, showing that the area has not been effectively washed.

CIP and SIP validation processes were one of the most critical aspects of the whole project: the cross-contamination risk running from one batch to another must be reduced to virtually zero. The tests IMA conducted gave positive results, confirming that the mass flow meter is an effective solution from this point of view too, thanks to the absence of moving mechanical parts, and to its stainless steel ducts with very low roughness.

View of the Xtrema LV showing the CIP/SIP circuit

Further advantages are related to the Micro Motion flow meters’ ability to handle versatile multi variable measures. For example, the detection of the temperature is an essential feature for certifying that inside the circuit, sterilisation has actually been achieved and the data set by the customer in process qualification (PQ) phase has been attained.The same flow mass measurement can be used to measure the amount of detergent used. Temperature, density and/or possible presence of foam in the flow measurement do not influence the system, the mass flow returns the exact amount of detergent that is passed along the circuit.

It is therefore easy to see how the batch change is faster than normal. In addition to not having to replace the pumps or any other mechanical parts, the washing and sterilisation phases are carried out without the need to dismantle measuring instruments and all in accordance with GAMP 4 guidelines and CFR 21-11 specifications.

The positive experience in the field has led IMA Life management to evaluate further developments linked with mass technology applications on aseptic processing filling machines.

The positive experience in the field has led IMA Life management to evaluate further developments linked with mass technology applications on aseptic processing filling machines

Basically, the Xtrema LV represents the top of IMA Life production range and the acceptance of a technological change, such as the one introduced via the Micro Motion mass flow, suggests that customers are able to see the benefits. In a few years’ time the measuring technology based on the Coriolis effect will provide the perfect system on which to base lower range machines too.

Proof of this is that time-pressure competition technology, which relates the dosed volume with a variation of pressure over time, though much evolved in recent years does not offer the same guarantees of accuracy as Coriolis Mass. The relationship between the dosed volume, time and pressure remains true only in the presence of laminar motion and it is well known that, for example, nozzles opening and closing creates turbulence.

‘In addition to being independent from density and temperature, the time-pressure technology that characterises the flow meters’ Coriolis force has been shown to be unaffected by fluid motion, whether it is turbulent or laminar. The measure is, in fact, related to the effective mass quantities in transit inside the instrument,’ says Ragazzini.

This article has been adapted from an article by IMA Life’s Ivan Ragazzini, HW-SW Technical Department Manager, IMA Life and Roberto Cazzaniga, Flow Product Specialist, Emerson Process Management.

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