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News and Events:

Filling

 

Here you will find answers to the following questions:

  • What clean room conditions are required for filling in an open container?
  • What is the difference between products sterilised in the final container and products filled in aseptic conditions?
  • What are the tasks of the various system components in the filling system?
  • What are the different types of filling systems and how are they evaluated?
  • Which steps are required to execute and control a filling process?
  • Which errors may occur?
  • How is it possible to prove the success of the aseptic filling method?
  • What needs to be taken into account when filling with powders?

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).

Figure 12.E-1 Advantages and disadvantages of different types of filling machine  

Advantages and disadvantages of different types of filling machine  

Linear filling machines

Routine technology

Space requirement

Rotary systems

High capacity, long fill time for individual objects

Complicated mechanics and pump control

Time-pressure filling
system

No pump, good cleaning

Dosage problems for different size containers and preparations, capacity/h

Weighing cubicle
systems

No pump, safe dosage

Complicated transport system, capacity/h

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.

Figure 12.E-2 Process for filling LVPs solution in cleanliness grade C 

Process for filling LVPs solution in cleanliness grade C

  • Check the bottle washing machine (acc. to checklist) and hot air tunnel, if applicable
  • Check pressure differentials between cleanliness grade C/cleanliness grade D and the immediate containers (release, batch, hydrolytic class, etc.)
  • Check that the reservoir/holding tank is assigned to the filling system (batch, date, preparation, final container)
  • Check the LF equipment (particle and flow rate measurement), documentation
  • Check the stoppers to be used (type, release, cleaning and sterilisation processes)
  • Check and calibration of the weighing apparatus for dosage control
  • Place the stoppers in the clean propellant vessel of the capping machine
  • Attach the cleaned and sterilised pumps, terminal filters and tube connections to the level vessel
  • Connect the solution feed, if necessary with a 0.2 mm/0.45 mm filter from the holding tank/reservoir to the level vessel of the filling machine
  • Start the pump function for self-priming and pumping out in a sample vessel for IPC of the integrity of the solution
  • Check the immersion depth of the filling needle in the object
  • Check the dosage amount
  • Check that the capping machine is functioning correctly (crimping)
  • Check the dosage measurement and torque control of the sealing cap
  • Enter documentation in the dosage control sheet
  • Fine dosage adjustment
  • Enter documentation in the dosage control sheet
  • Start of filling, dosage control and documentation after release by the IPC lab
  • Test the sealing cap, documentation
  • End of filling
  • Check the LF equipment (particle and flow rate measurement), documentation
  • Compare number of items/supplied quantity of solution, consumption of bottles and sealing caps
  • Disassemble pumps, tubes and level vessel for cleaning and sterilisation, for CIP/SIP, switch connections for WFI, steam and compressed air feed
  • Clean and disinfect machine surfaces

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.

Figure 12.E-3 Possible faults when filling infusion bottles / vials  

Possible faults when filling infusion bottles/vials  

Possible faults

Cause/prevention

Solution flowing into the bottle sputters at the end of the filling needle

  • Pump fill pressure too high (machine speed)
    -> Reduce machine speed
  • Cross-section of the filling needle too small
    -> Use needle with a larger cross-section

Solution forms too much foam on the surface.

  • Drop height of the solution into the bottle is too high
    -> Lower the filling needle into the bottle
  • Filling needle too close to the bottom of the bottle
    -> Soften the impact of the solution by lifting the filling needle
  • Temperature of the solution is too high
    -> maximum 30 ºC

Filling needle drips

  • Pore size of the needle filtration sieve is too small
    -> Choose larger pores or mesh size
  • Reverse suction effect of the pump is too small
    -> Increase time for pump reverse suction (reverse suction route in the needle 1 to 3 cm)

Temporary dosage fluctuations

  • Suction conditions have altered due to stiffness of pump and tailings of solutions
    -> Ensure the pump and valve control are running smoothly and check the fill level control in the level vessel

Dosage changes

  • Change in machine speed and thus suction conditions
    -> Reset the pump dosage

Stoppering is too difficult (incomplete)

  • Fit between the bottle neck diameter/stopper diameter is too narrow
    -> Measure the containers and stoppers
  • Adhesive power between the stopper material and glass is too high
    -> Increase the moisture level of the stoppers and bottles (if necessary, use siliconisation)

Stoppering is too easy (stoppers are ejected by air bubbles)

  • Fit between the bottle diameter and the stopper is too wide and too moist.
    -> Measure the containers and stoppers, use drier stoppers and bottles (if necessary, increase the blowing out of the bottles with compressed air and ensure that the bottle opening does not become wet from the solution)

Crimping incomplete, not tight enough

  • Too little side material, too little downwards pressure on the cap
    -> Increase pressure of the plunger
  • Incorrect roller alignment of the crimping head

Crimping deforms the aluminium cap

  • Pressure on the cap is too high, material overhang on the bottle neck
    -> Reduce the pressure on the plunger, check the roller position of the crimping head

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.

Figure 12.E-4 Filling process in cleanliness grade A/B  

Filling process in cleanliness grade A/B

  • Check the ampoules supplied in hygienic packaging (release, batch, quantity, size, etc.)
  • Check the washing machines and the hot air sterilisation tunnel according to the checklist (media pressures, temperatures, capacity specification, etc.)
  • Start the equipment (normally located in cleanliness grade D)
  • Check the pressure differential between cleanliness grade B/grade C/grade D
  • Assemble the filling equipment (pumps, hollow needles, tubes, filters for nitrogen gas and solution distributor
  • Check (in operation) the LF in cleanliness grade A, particle measurement, flow rate, microbial count determination using the air sampler method, CFU determination of the machine surface in contact procedures
  • Check (in operation) the environment in cleanliness grade B using the air sampler method and for contact procedures, check equipment surface and floor, as well as particle measurement. The filling container/reservoir is usually in cleanliness grade B close to the filling machine or, less commonly, in cleanliness grade C in the case of ongoing sterile filtration into cleanliness grade B in a level vessel.
  • Control and calibration of weighing apparatus
  • Aspiration of the solution into the solution distributor by starting the filling pumps or by using a vacuum pump for smaller fill volumes and relatively long pipelines with a relatively large tube diameter
  • Set the filling speed
  • Pump solution from the hollow needles as a preliminary run into a sample vessel for IPC and for general dosage settings
  • Control the immersion depth and centring of the hollow needles in the ampoules
  • Dosage measurement, documentation in the dosage log, and balance printout
  • Fine adjustment of dosage, documentation in the dosage log, and balance printout
  • Control CFU determination, personnel fingerprints in grade B
  • Adjust the flame settings in the tip sealing station
  • Start filling following release by IPC lab
  • Check the ampoule seal, glass ampoule shape and purity
  • Check dosage, document in the dosage log and balance printout
  • Send filled and sealed ampoules to IPC lab
  • Remove filled and sealed ampoules in steel magazines, attach a label with a consecutive number, preparation, batch, etc.

End of filling

  • Check the environment:
    CFU determination by way of contact procedure - grade A machine surface in LF
    CFU determination by way of contact procedure - grade B surfaces (tables, balances, exterior of filling machine)
    CFU determination by way of contact procedure - grade B floor
  • Personnel controls:
    CFU determination by way of contact procedure - cleanliness grade B fingerprints
  • Disassemble pumps, tubes, solution distributors, etc.
  • Clean the filling machine, disinfect surfaces, disinfect floor

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.

Figure 12.E-5 Possible faults when filling ampoules  

Possible faults when filling ampoules

Possible faults

Cause/prevention

Ampoule neck becomes wet from solution

  • Incorrect positioning (centring) of the filling needle
    -> Check the centring and alignment of the filling needle bar
  • Filling needle is bent
    -> Straighten the needle

Bubbles or foam form on the solution surface in the ampoule

  • Pump fill pressure is too high
    -> Reduce machine speed
  • Cross-section of the filling needle is too small
    -> Choose a larger cross-section
  • Drop height of the solution into the ampoule is too high, insufficient low level filling
    -> Reduce immersion depth of the needle
  • Filling needle is too close to bottom of ampoule
    -> Increase distance between filling needle and the bottom of the ampoule.

Drop formation on the filling needle

  • Reverse suction effect of the pump is too low.
    -> Change the control of the reverse suction effect.
  • Pressure tubing to filling needle is too long ("breathing")
    -> Shorten the tube, use harder material if necessary
  • Pump is leaking
    -> Replace the pump

Ampoule lance has incorrect shape:
Bubble head

  • Temperature of the solution is too high
    -> Reduce solution temperature
  • Solution wets the lance part and evaporates
    -> Check the centring and shape of the filling needle
  • Tip sealing flame is too hot
    -> Reduce gas supply
  • Solution is too cool (slight vacuum effect)
    -> Bring solution to room temperature

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.

Figure 12.E-6 Warning and action limit depending on the number of filled containers

No. of filled containers

Alert limit

Action limit1

3,000

Not applicable

1

4,750

1

2

6,300

1

2

7,760

1

4

9,160

1

5

10,520

2

6

11,850

2

7

13,150

3

8

14,440

3

9

15,710

4

10

16,970

4

11

1 Media fill failed.

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.

Figure 12.E-7 Execution of a media fill

Execution of a media fill

  • Pump two large quantities of solution (approx. 500 ml) into sterilised glass containers (for example, beakers) for incubation and inoculation with organisms to test for growth. This can be used to ensure that the equipment is sterile and the personnel performed the assembly procedures properly.
  • Control CFU determination, personnel fingerprints in grade B
  • Take fingerprints from all employees in cleanliness grade B and in the planned interventions and samples (must be described in detail in the SOP for media fill).
  • Stop the machine, remove 10 to 20 objects before, at, and after the filling point, loosen and tighten the hollow needle, restart the filling machine, set the dosage, and after filling and capping the first subsequent ampoules, remove them as a sample and perform an additional incubation and assessment. All this should also be included in an SOP to be created by the unit.

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.

Figure 12.E-8 Possible faults when filling with powder

Possible faults when filling with powder

Possible faults

Cause/prevention

  • Tailings of powder from the reservoir faulty
  • Fill level in reservoir is too high, causing too much weight and reduced vibration of the coupling system -> Reduce the fill level
  • Faulty flow properties of the powder, humidity is too high? -> Test
  • Change in particle size? -> Test
  • Adjust pipe diameter or insufficient column width of the reservoir to the coupling system
    -> Adjust the settings
  • Machine switches off due to insufficient powder feed
  • Fill speed of the machine is too high
    -> Reduce or adjust speed

Summary

This section describes the main functions of a filling system and explains the necessary system components and their technical/physical tasks. Possible faults are discussed together with their causes and prevention. The execution of the operating steps for filling containers in grade C and grade A/B environments in a systematic process is described.

The section also describes the process of a nutrition agar fill, as well as the background behind the procedures and further microbiological processing.

Special systems are required for filling containers with powder. Particular attention has to be paid to particle load in the air resulting from the powder product.



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