Filling

 

12.E.1 Filling equipment for solutions

The solution exists as a batch in the storage container (filling container) and has been filtered and released for further processing. The containers to be filled are cleaned, sterilised, and depyrogenated, and are transported to the filling machine by conveyor belts or manually from magazines. The containers are filled with solutions by machines specifically designed for this purpose, which are available from several manufacturers. Filling systems have undergone considerable changes in recent decades, particularly in terms of their electronic controls. The main differences when compared with single and double-figure ampoule and bottle filling machines with dosage pumps are as follows:

1. Linear filling machines or rotary systems with several filling points and weighing cubicles

2. Filling machines with time-pressure filling systems and turbines

There are advantages and disadvantages to all machines, which differ according to fill quantity per object and solution properties of the solution, and a system must be selected based on these properties (see figure 12.E-1).

Other important points are: Viscosity, density and solid matter content of the solution. These parameters influence the flow rate in piping, pumps, and hollow needles for filling objects, and thus affect the time required to fill each object. These parameters are used to calculate the filling capacity of a machine.

12.E.1.1 System structure

A dosage filling system (piston dosing), consisting of a solution container, pump and final container must include the following components:

• Storage vessel (or container), containing the solution to be filled
• Level vessel in which smaller quantities of the solution are kept for the pump system
• Solution distributor (feed to individual pumps)
• Valve mechanism for controlling the aspiration/pressure phase of the pumps
• Piston dosage pump (or pump with integrated aspiration or pressure configuration)
• Hollow needle for filling the final container
• Connecting pipes (stainless steel) or tubes (for example, silicone, teflon, etc.) for liquid flow in all system components.

Self-priming pumps are used in all cases apart from the time-pressure filling system, which does not use any pumps.

The function of each system component is described in the following:

Storage vessel

Stores the solution in the tank and maintains temperature at room temperature (occasionally at higher temperatures during filling). Transports the solution due to constant gas pressure (filtered nitrogen), if necessary via organism-particle filters, into the level vessel of the filling machine.

Level vessel

The level vessel is made from stainless steel or glass and has a valve mechanism that guarantees a maximum and minimum level of liquid in the vessel with no pressure. The difference in the liquid level compared to the aspirating piston dosage pumps should be no more than minus 60 cm. The aspiration pressure of the pumps can be increased or decreased by setting the level vessel at different heights (can also be positioned using the pumps).

Solution distributor

These are small containers (0.5 to 10 l), from which the connected pump pipes or tubes suck the quantity of solution directly into the pump. Due to the negative pressure that forms in the solution distributors, they extract solution from the level vessel and refill themselves in time for the next work cycle. A solution distributor is therefore not required if the level of liquid in a storage vessel is approximately equal to or greater than that in the pumps. In general, however, this does not apply, since the level of liquid in the storage vessel is usually drastically reduced during the filling process. This means the height difference becomes too great for suction to be possible.

Valve mechanism (cursor)

The aim of the valve mechanism is as follows: To establish a suction channel from the solution feed to the pump cylinder on retraction of the piston in a synchronised cycle. Then, at the peak of the movement, to shut off the suction channel and open an outflow channel to the filling needle. On forward propulsion of the piston by the cylinder, the previously extracted quantity of solution is ejected towards the filling needle. At the end of the piston movement, the outflow channel is closed and the suction channel is quickly reopened (back suction).

Piston dosage pump

On the intake stroke of the piston movement in the cylinder, the piston dosage pump takes up a certain quantity into the cylinder space created and, after the cursor has switched position, ejects it via the (adjustable) set route. The primary aim is to always eject the same set quantity. A metering accuracy of £0.5 % should be achieved in order to fulfil the requirements of the pharmacopoeias (USP, JP, EP). The material for the piston dosage pumps can be selected from stainless steel, ceramic, glass, or combinations with seals. The selection of the material depends on the dosage volume and the long-term stability. An important factor is whether the pumps in an installed state can be cleaned (CIP) and sterilised or steam-treated within the machine (SIP). For pumps made from stainless steel and ceramic, this procedure is the state of the art. In cases in which pumps and pipes have to be dismantled and taken apart after use, the individual components are cleaned in accordance with an SOP and sterilised before re-use (steam sterilisation or dry heat sterilisation for glass accessories). CIP/SIP treatment (cleaning in place/sterilisation in place) of pumps, pipes, and filling needles almost always includes simultaneous cleaning of the solution feed from the storage vessel, since this is the point at which the WFI and steam for cleaning are connected and supplied. The CIP/SIP procedure is then carried out controlled by a program (see chapter 4.I CIP (Cleaning in Place)).

Hollow needle (filling needle)

Hollow needles for filling containers are selected in different diameters according to the solutions to be filled (viscosity, foam characteristics, flow rate and surface tension), and depending on the container opening. In general, these are pipe sections with a diameter of 2 to 10 mm. When the hollow needle is inserted into the container, the solution should be squeezed into the container (ampoule/bottle) in the pressure phase of the pump piston. Turbulence in the existing solution in the container should be minimised in order to avoid foam formation. Foam means that when the bubbles burst, droplets of liquid land around the neck of the bottle, where they are pressed on the lateral seal surface of the stopper. This may result in crystal deposits, which can enter the solution as crystallisation inducer.

Foam formation in the filling phase of an ampoule is even more serious, since the chimney effect of the rising air carries foam bubbles through the glass ampoule, and they precipitate around the tip seal. This effect also occurs after the end of the filling phase, when a larger foam layer remains on the surface of the fluid. The rotation phase at the tip sealing station causes the foam bubbles to burst, and the liquid droplets slide into the glass ampoule where they dry out or even become charred. In the subsequent steam sterilisation process, these cracked solution ingredients are then rinsed in the solution and lead to a directly visible and detectable reject. It is even worse if these dried substances are not removed until after the optical control. Suitable measures must be introduced to prevent these problems as far as possible. A deciding factor can be to reduce the rate at which the solution flows from the needle into the container. To reduce this rate, it is necessary to employ a combination lower filling pressure and the largest possible diameter of filling pipe. It can be advantageous to start the first phase of filling quickly and to fill more slowly towards the end of the filling quantity (mechanical-technical filling characteristics of movement control of the filling pumps).

Connecting lines/tubes

Connecting lines (pipes) for transporting the solution should always be used if there is no movement involved and the machine can be cleaned in its installed state. Tubes must be used at points in which constant synchronised motion is required (for example, the lifting and lowering of a filling needle attached to a tube), and at points in which the filling equipment has to be disassembled or partially disassembled for cleaning and sterilisation. From a technical flow perspective, tubes have to fulfil the same task as fixed connecting lines (pipes). This means that the composition of tube walls must be a stable shape, and changes in the volume of the tube under pressure must be kept to a minimum (there must be a minimal "breathing" effect).

Time-pressure filling system

This type of dosage of solutions into a container requires an exact, very fast measurement method and calculation of the opening time phase of the cut-off mechanism against which the solution flows. The cut-off mechanism can be a method for squashing a silicone tube, a membrane valve, or a mechanical cursor. The required accuracy is the most important factor in the selection of a cut-off mechanism, which means that the options of membrane valve or mechanical cursors are less frequently considered. Due to the required dose accuracy, time-pressure filling systems are only useful for amounts greater than 50 ml. It is important to remember that the preliminary pressure (nitrogen or compressed air) created to transport the solution through the opened cut-off mechanism and the hollow needle into the container must be sufficient to force an excess of solution (volume) through the hollow needle within the residence time of the container under the hollow needle. Switching the cut-off mechanism limits the quantity of solution. The opening time of the cut-off mechanism is therefore dependent on the current density (according to the solution temperature) of the transported solution. This must be controlled in a computer-controlled pressure/density/temperature relationship. If processing several different solutions (preparations) and container sizes, the applicability of this system is limited. If filtration (of particles and organisms) or different-sized containers (tanks) and different lengths of piping are then also used, problems will undoubtedly arise. The advantage of this system is the complete absence of pumps and hence the associated problems

Weighing cubicle

The principle is the initial weighing into the container and the switching of the filling process by the weighing cubicle. The dosage is measured for each container and maintained by constant monitoring. This controls the filling system. However, the system involves expensive transport systems to the weighing cubicle and zeroing and weighing each container takes time, which means that capacity is limited. All other problems of a filling system, such as cleaning, partial dismantling, and sterilisation, also remain. No pumps are used. Other tasks that are usually fulfilled by a pump are performed by exerting a preliminary pressure on the solution in the supply tank to the on/off valve, which is controlled by the weighing cubicle.

Filling turbines

The fill solution flows through the turbines within the predefined pressure range, for example 1 to 2 bar, and the revolutions (converted to volume) are "opened" and "closed off" according to the dose. In my experience, the technology is not yet sophisticated enough in the range from 5 to 20 ml.

12.E.2 Process for filling LVP containers in cleanliness grade C

Figure 12.E-2 shows the individual steps required for filling in a facility for LVP (Large Volume Parenterals) in cleanliness grade C. Dosage controls should be performed hourly, and half-hourly for high capacity machines. An additional dosage control should also be performed for every anomaly.

When using CIP/SIP systems, the first activity is usually to attach several pipe and tube connections to the pump system, since this is how the WFI, steam and compressed air are supplied. Figure 12.E-3 lists possible faults and information on their cause and possible prevention.

12.E.3 Process for filling ampoules with solution in
cleanliness grade A/B

Figure 12.E-4 describes the filling process in cleanliness grade A within a grade B environment as it is prescribed for aseptic manufacturing.

12.E.4 Filling ampoules in cleanliness grade C
and laminar flow

This work area is used for solutions that are sterilised in the sealed ampoule. All steps described for filling ampoules in a grade A/grade B environment (see figure 12.E-4) must be executed, with the exception of microbiological tests, since there are no batch-specific tests for cleanliness grade C. In general, these are monitored weekly or at other regular intervals as a part of quality control. Different limits also apply (see chapter 12.G Microbiological monitoring).

Figure 12.E-5 shows the possible faults that can occur when filling ampoules.

12.E.5 Culture medium filling (Media Fill)

After the three media fills for validation, a nutrition agar fill should be performed at regular intervals, since this is the only way to definitely prove the aseptic filling technique. This control is necessary due to the large number of process steps involved in an aseptic operation and possible deviations from the ideal requirements in terms of personnel, activities, environment, media and equipment. Routine monitoring of normal production provides only a snapshot of the operating status.

The 2004 FDA guideline on aseptic technique (chapter D.10 Guidance for Industry Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice) states that after validation, a media fill should be performed twice yearly.

The culture medium should enable growth of the widest possible spectrum of organisms. The medium, for example, casein soya bean digest broth, should have a low selectivity and be recommended by a pharmacopoeia (for example, USP). For culture medium filling (media fill), all the same activities are required as for grade A ampoule production in a grade B environment (see figure 12.E-4), but under worst-case conditions. This means the slowest fill speed (containers and solution are exposed to environmental conditions for longer), planned interventions (multiple), as they can occur in the case of faults in normal production, and maximum presence and activity, for example, of technical personnel. A minimum number of 3000 filled containers is required. For a confidence level of 95%, none of the containers must be contaminated. It is therefore common practice to fill a minimum of 4750 containers. The alert threshold limit is then 1 contaminated container, with an action threshold limit of two contaminated containers (see figure 12.E-6).

If you consider that a modern system can fill 120 to 300 ampoules per minute, this would mean a time period of just 10 to 25 minutes. This is a short time period for assessment. In addition, it is difficult or impossible to allow filling cycles and tip sealing processes to run as slowly as possible. These operations can then not be correctly executed and, due to the properties of the culture medium solution, lead immediately to filling errors, breakage of glass containers, and insufficient tip sealing. In practice, therefore, a slow fill speed is selected at which all functions can still be guaranteed, and the planned interventions and number of items correspond to a runtime of approximately one hour. Added to the set-up and set-down times for the media fill, this requires a time period of over two hours. The work required for the subsequent microbiological processing, such as incubation and quality control (visual control) then remains reasonable and provides a realistic process simulation.

The culture medium solution for the medium fill is treated in exactly the same way as the product, i.e. it is generally sterile-filtered. It may be necessary to heat the culture medium solution, as otherwise the filters can quickly become blocked. Connections to the filling equipment tubes should be made under LF.

The ampoules are filled as described in figure 12.E-4 Ampoule filling in cleanliness grade A/B. Additional and variant steps are shown in figure 12.E-7.

The manufacturing instructions for the media fill include the time specifications and conditions for incubation of the filled objects (for example, normal or upside-down), and the results protocols of the incubated objects in the individual magazines.

If non-sterile objects are identified, you can narrow down the time the sample was filled, and note any peculiarities that occurred within this period (intervention? dosage control? dosage change? unplanned stop due to washing machine or sterilisation tunnel fault? etc.). The results of analysis of the non-sterile objects for microbial species are documented in the manufacturing instructions.

Microbiological results and assessment

Calculation of the proportion of non-sterile objects following incubation of the filled containers (see figure 12.E-6): Target <0.1 %.

CFU determination at the monitoring points in the grade B filling room (surfaces, floor, air).

CFU determination at the monitoring points (see chapter 12.G Microbiological monitoring) of personnel and material locks in grades C and B (air and surfaces).

Yield calculation, assessment and release by management.

12.E.6 Filling with powders

Sterile powders are normally obtained from sterile filtered solution by spray drying or crystallisation, milled, micronised (if applicable), mixed with lubricants and additives and, if necessary, sterilised with dry heat or gas. The properties of the powder, such as fluidity, bulk density, dust production (abrasion), sensitivity to moisture, and the type of containers to be filled, are determining factors for the construction of the filling machine used.

Two basic variants are possible:

• Machines that use a feed shoe to mechanically fill a mold with a certain quantity of powder and eject or blow this out into the specified container.
• Machines that transport powder to the container in the weighing cubicle via vibrating rails until the planned preset dose is reached, then automatically stop the conveying and transport the next container for filling.

The requirements for a machine for powder filling are just as demanding as for a filling machine for solutions. Particular attention must be paid to the areas of cleaning, assembly and disassembly of components, and the flow profiles of air due to particle load from the contents.

It should also be possible to perform a culture medium fill instead of, or in combination with, the powder to provide evidence of aseptic manufacturing methods.

12.E.6.1 System layout of the filling equipment

A system for filling containers with sterile powder usually consists of the following components, which are used for the functions described below:

Reservoir

Storage of the powder during filling. Feeding powder into the filling system through the vibration facility on the reservoir or helical conveyor.

Coupling system, helical conveyor, vibration piping

The system must enable containers to be connected, and in some cases replaced, under LF (possibly outside of the machine LF).

Feed shoe for molds - vibrating bars

The feed shoe must fill a space in the mold with powder in accordance with the required dose. A vibrating bar or a vibrating pipe transports powder to the designated container through adjustable vibration (time and amplitude) and gradients. The vibration time is controlled by the dosage balance.

Aspiration system for developing dust

Apart from the usual grade A environmental conditions used for aseptic filling, the build up of dust cannot be avoided when filling containers with powder, and it is not possible to comply with the acceptable particle count for ISO class 5 (previously class 100 209E) "in operation" at any point in the LF. This means that an aspiration system for dust is required at transition points between the feed shoe and the mold or the vibration pipes. This aspiration may have a slight influence on the laminar stream in the LF, but it limits the particle load at these points. A transportable suction system (vacuum cleaner for the ISO class 5 clean room area ) must be available in case of faults in the production process.

Weighing system - vibration conveyor

Start the vibration conveyor after weighing and zeroing the empty container. Switch off depending on the set dosage.

12.E.6.2 Practical process using a glass bottle as an example

The process should be performed in accordance with a valid SOP. The filling takes place in grade A conditions within a grade B environment.

• Check the bottle washing machine (acc. to checklist) and hot air sterilisation tunnel.
• Check pressure differentials between cleanliness grade C/cleanliness grade B and the immediate containers (release, batch, hydrolytic class, etc.)
• Check the reservoir(s) (batch, date, preparation, assignment to filling equipment and immediate container, and sterilisation seal).
• Check the LF equipment (particle and flow rate measurement), documentation.
• Check that the aspiration system of the filling machine is functioning correctly.
• Check the seals for the immediate containers (type, release, cleaning and sterilisation processes or ready-to-use documentation).
• Check the calibration of the balance equipment for dosage and for a system check.
• Stock the capping system with seals.
• Assemble the cleaned and sterilised product-stirring filling mechanism
• Connect the reservoir under LF to the coupling system
• Control (in operation) of the LF grade A, particle measurement, flow rate, CFU determination using the air sampler method (see chapter 12.G Microbiological monitoring), CFU determination of machine surface by way of the contact procedure.
• Control (in operation) of the grade B environment using the air sampler method and contact procedure on equipment surfaces and floors, and particle measurement of the air.
• Start the conveying and filling mechanisms
• Check the dosage amount
• Check that the capping unit is functioning correctly
• Set the dosage
• Control, CFU determination, personnel fingerprints in grade B
• Start filling following release by IPC
• Check the dosage and documentation (automated using the weighing system when using vibration conveyor and weighing cubicle)
• Output of filled and sealed containers in subsets (magazines) with label containing consecutive number, preparation, batch, etc.

End of filling

• Microbiological environmental monitoring of the following positions:
• in grade A, machine surface in LF
• in grade B, working surfaces (e.g. exterior of filling machine, tables, etc.) and floors, fingerprint of personnel
• Disassemble the feed hopper
• Clean the filling machine, disinfect surfaces, disinfect floor surfaces.

Figure 12.E-8 lists the potential faults, together with possible causes and prevention or testing methods.