Here you will find answers to the following questions:
- What are the main container materials used in primary packaging?
- Which agents are used to wash final containers?
- What particle and microbial content requirements are the cleaning agents expected to meet, and how are these achieved?
- Which temperatures and quantities of cleaning agent are required and which functional steps are necessary in automatic washing?
- Which changes to the surface should be noted?
- Which washing procedures are common practice?
Stoppers for sterile pharmaceutical products must fulfil the requirements listed in figure 12.D-1.
Figure 12.D-1 Requirements of stoppers
Requirements of stoppers
- Of a suitable hardness, dimensions, and shape for the purpose
- Pre-cleaned by the stopper manufacturer to minimise the presence of fill material residue, colour pigments, and plasticisers
- Must not absorb any of the "packed" pharmaceutical product
- Must not release any substances into the pharmaceutical product
- Smooth surfaces and clean cut edges
- Minimum friability
Stoppers for pharmaceutical purposes are usually made from rubber (vulcanised natural caoutchouc). Due to its high elasticity, the material provides a very good seal against the surface of the bottle neck. The high durability against wear also enables multiple piercing of the stopper without fragments breaking off. The material can be sterilised in super-heated steam, is free from toxic ingredients, and can be cleaned with relative ease. The material can be coloured and produced in varying degrees of hardness. Natural rubber and its synthetic derivatives - butyl or chlorobutyl rubber - are sufficient to meet the relevant application requirements in 90 % of cases.
Any applications for which the requirements are not fulfilled with these elastomers either have very specific requirements (for example, high temperature tolerance, resistance to mineral oil, etc.), or are subject to maximum requirements for safety reasons (for example, seals for test substances, absolute physiological safety, or similar). These problems can be solved by using Teflon-clad stoppers or silicone rubber. The term "silicone" is not applied uniformly. Sometimes it is used to refer to all silicon organic compounds, while sometimes it is used as a more precise definition for certain types of Si bonds. These are synthetically produced polymer compounds in which hydrocarbon residues (usually methyl groups) form long chain, sheet, or spatial structures with silicon atoms, bound by oxygen bridges. The compounds are heat-tolerant, hydrophobic, isolating, not very volatile, not flammable, and barely change viscosity in the case of temperature fluctuations. Depending on the length of the molecular chains and the degree of interlinking, materials are produced in varying states of liquid "silicone oils" or solid "silicone rubber". This material is most commonly used for tubes and gaskets. Silicone rubber is mostly obtained from a reaction between silicon and methyl chloride (Rochow process). The resulting chlorosilane is then fractionated, followed by hydrolysis, condensation, or polymerisation. The beneficial properties of silicon compounds are summarised in figure 12.D-2.
Figure 12.D-2 Properties of silicone compounds
Properties of silicone compounds
- Heat and cold resistance
- High tensile strength
- Physiological indifference
- Resistant to ageing
- Long lifespan
- Hydrophobic behaviour
- Surface activity
- Smooth surface
- Low proportion of volatile substances
Quality and purity are the priority aims of manufacturers who guarantee "pharmaceutical quality". This includes clean room conditions and compliance with standards and internal regulations.
All materials are tested and each of the production steps roling, mixing, shaping, and vulcanising are monitored according to precise specifications. All shaped (punched) stoppers undergo a final inspection. The stoppers are cleaned. Each manufacturer has their own procedure. Since shaping the stoppers in metal trays requires the use of separating media (usually silicone oils), manufacturers must ensure that all traces of any separating medium are removed. The final state of the stoppers after cleaning depends on the cleaning procedure and the cycles used.
12.D.2 Particulate impurities
Attempts to keep stoppers 100 % particle-free by washing are illusionary, due to the elastic nature of the material and its affinity towards particles from the shaping environment. Stoppers can only accurately be described as low in particles. The determination of the number and size of particles on a stopper is a very time consuming and complicated process. The total displacement of particles from the stopper in a washing fluid for particle measurement is necessarily performed as a separate procedure. Once no further particles are displaced from the stopper into a washing fluid specifically designed for this purpose, it is unlikely that the product itself will displace any further particles from a stopper. Of course, this must be proven in comparative studies.
Only the lower part (approx. one third of the stopper surface) of the stopper used in the final container is moistened by the solution, and the stopper can only shed particles in this area.
If the stoppers are sterilised in a steam steriliser (sterilisation bag), the particle status of the stoppers changes once again. The influence of the transport system on the filling machine is also significant for the stoppers (particle emission due to shear forces in the propellant vessel).
It is important that the particle load of the individual stopper must only cause a slight change to the particle content of the pharmaceutical solution in the range of 10 mm/ml and 25 mm/ml (see figure 12.D-3).
Figure 12.D-3 Particle load limits
Particle load limits
for example 20 ml vial (SVP)
for example 100 ml infusion bottle (LVP)
Maximum permitted particle count:
6000 P ³ 10 mm
600 P ³ 25 mm
Maximum permitted particle count:
25 P/ml ³ 10 mm
(corresponds to 2500 P/100 ml container)
3 P/ml ³ 25 mm
(corresponds to 300 P/100 ml container)
(The Japanese pharmacopoeia requires 2 P/ml ³ 25 mm.)
The theoretical causes of particle load in a solution are as follows:
a) Particles from the solution
b) Particles from the laminar flow (LF) air
c) Particles from the internal surface of the final container, which were not removed in the washing procedure (can be determined with the use of suitable laboratory procedures).
d) Particles from the surface of the stopper that comes into contact with the product
Re. a): Particles from the solution (filtered over 0.2 mm membrane filter and 8 to 30 mm needle filter) can be easily measured and are generally not significant. These filtrations minimise a particle count of over 10 mm to far below the permitted particle count.
Re. b): Particle load from the controlled laminar flow (cleanliness grade 100) can be eliminated, because no particles larger than 5 mm are present in the air.
Therefore, only c) and d) are likely influencing variables.
If you want to evaluate the influence of the stopper washing procedure, this must be compared to the particulate quality in the final container for (c) (unless the cleaning is just performed "as well as possible"). During the filling process, final sterilisation, transport, etc., these particles are also shed into the product.
The required quality of the particulate purity of the Final Rinse (WFI 25 P/ml ³ 10 mm and 3 P/ml ³ 25 mm) provides a good basis for the calculation.
Residual moisture (WFI) in containers of sizes between 2 and 250 ml after blowing out with particle-free air is present in quantities ranging between 10 and 150 mg, which corresponds to a particle load of 5 particles ³10 mm and 0.6 particles ³25 mm per object. This is therefore negligible compared to the permitted level of 6,000 particles ³10 mm and 600 particles ³25 mm per container and for 100 ml infusion bottles, 2,500 particles ³10 mm and 300 particles ³25 mm per bottle.
Re. d): The nature of an elastomer and its manufacturing process means that its surface is subject to higher particle load than, for example, a glass surface. It can be assumed that approx. 80 % of the particle load of a product is caused by the stopper sealing system (teflon-clad stoppers show better results).
12.D.2.1 Stopper washing
The washing process must be executed in accordance with a valid SOP and must be incorporated as a work step in the manufacturing instructions.
Reasons for washing stoppers in pharmaceutical operations include:
- The (particulate and microbiological) cleanliness of the stoppers is ensured by your own validated processes.
- The time from cleaning to use can be planned, to guarantee microbiological quality.
- The unification of the surface properties enables bottles to be processed on sealing machines (this is often the main problem with faster filling machines). It is important to keep a detailed record of the delivery status of the stoppers by implementing a goods in check and monitoring.
To remove the particles from the surface without affecting the properties of the stopper, the conditions listed in figure 12.D-4 must be fulfilled.
Figure 12.D-4 Stopper washing
- Washing fluid made from purified water (if necessary with tenside for improved surface moistening)
- Temperature of the washing fluid as high as possible (minimum 70 °C)
- Determine the percentage quantity of the washing fluid/number of stoppers
- Continual separation of particles from the washing fluid by filters (pore size 2 mm) using a circulation pump
- Stoppers moved with minimum friction (if possible, flotation) of the stoppers to prevent any surface changes
- Apply as many boundary layer influences as possible (air/liquid/steam) to the surface of the stopper, which increases the cleaning effect
- Rinse phases and final rinse >80 °C for microbial reduction
- Sterilisation or steam overlay for microbial reduction
These essential cleaning steps are executed with the help of washing machines that control the use of media and include programs to regulate the chronological sequences. Washing machines for this purpose are supplied by several manufacturers. Separate wash programs can be defined and validated depending on the type and quantity of the stoppers (freeze-drying stoppers, injection stoppers, infusion stoppers, etc.). The washed stoppers should be removed from the washing machines into washed and, if necessary, sterilised containers. Stoppers that need to be sterilised in autoclaves should be placed and heat-sealed in particle-free sterilisation bags. Since these washing machines are very expensive and can be laborious to operate, and the quality of the washed stoppers has to be constantly monitored, as an alternative, "ready-to-use" stoppers can be purchased from the manufacturer (accompanied by the appropriate certificate).
12.D.3 Glass containers (ampoules, bottles)
12.D.3.1 Types of glass
Glass containers for pharmaceutical contents are manufactured in glass of varying composition, and are classified into hydrolytic (water resistance) classes 1, 2 and 3. This classification is necessary, since the pharmacopoeias of different countries require that injectible products must only be filled in containers whose hydrolytic surface resistance meets the requirements of glass type 1 (hydrolytic class 1). Glass containers in accordance with hydrolytic class 1 are also known as borosilicate glass, and hydrolytic classes 2 and 3 are known as soda glass. To achieve the hydrolytic classification, the glass must contain a specific mixture of components, which indicates the hardness of the glass as well as the behaviour of the surface in contact with the filled product. It has been determined that the temperatures required for processing glass to make containers cause changes to the internal surface that can have a negative effect on the filled product. This mainly refers to the vaporisation of Na2O that collects on the internal surface. In aqueous solutions, this can lead to changes in the pH value and other interactions. The internal surface of the glass therefore has to be processed. This improves the hydrolytic class of the internal surface, for example, from class 2 to class 1. To improve the hydrolytic class, the glass is treated with ammonium chloride (or ammonium sulphate). During the expansion process at approx. 580 °C, the Na2O residues form a chemical compound with the coating material, which gives the surface a slightly milky appearance. This coating can be easily removed in the initial washing phases during normal cleaning procedures.
Two different procedures are used for manufacturing containers:
- Deformation of glass pipes for ampoules of between 1 and 50 ml and bottles between 5 and 30 ml.
- Production from molten glass by glass blowing, for bottles between 50 and 1000 ml.
Manufacturers of glass containers for the pharmaceutical industry have fulfilled the basic regulations of the GMP requirements by setting up clean rooms after the tempering oven (580 °C) for packaging with plastic trays and cartons in shrink film. It is essential to use a clean room or an LF box for the steps Wrapping in film, Heat sealing and subsequent shrinking, to keep the levels of organisms and particles as low as possible. The different types of packaging are commonly known as safe-pack, hygiene-pack or clean-pack.
The washing processes for ampoules and bottles take place upstream of the filling process in compact lines. These systems consist of a combination of washing machine, sterilisation tunnel, and filling machine. The washing machines are designed as rotary or bar-based systems. The media used are filtered compressed air (0.1 mm), purified water or a WFI connection for supplying the circulatory water (7 mm/2 mm filtration). WFI is prescribed for the final rinse (with a particle filter 20 to 30 mm against particle emission through valve seals and abrasion from pressure pumps). The cleaning procedure comprises the steps listed in figure 12.D-5
Figure 12.D-5 Cleaning procedure for containers
Cleaning procedure for containers
- Blow out with compressed air (0.1 mm particle filtration) or outlet (for infusion bottles with large bottle necks)
- Spray inside and out with purified water via nozzles (using approx. one third of the object volume per spray cycle)
- Blow out with filtered compressed air
- Spray with filtered, purified water
- Spray with filtered compressed air
- Spray with WFI (final rinse, 20 to 30 mm particle filtration)
- Blow out with filtered compressed air
The use of ultrasound in the first stage of the cleaning procedure (the object is filled and transported immersed in water) has been demonstrated to contribute the mechanical detachment of impurities due to a "cavitation" effect (implosion of hollow spaces in the water created by the ultrasound).
When spraying with filtered, purified water, you should ensure that the water can also drain away within the available time phase, as otherwise, only rinse water that contains particles circulates in the object and the particles are not rinsed off in the water.
It is important to use a quantity of rinse water corresponding to approx. 1/3 to 1/2 of the object volume, to ensure that the boundary layer effects of air/fluid can be allowed to act on the internal surface. The number of spray processes depends on the requirements of the pharmaceutical manufacturer.
All washing processes must be validated.
Since the overall washing effect results from the parameters listed in figure 12.D-6, all these parameters must be determined and validated.
Figure 12.D-6 Validation parameters for washing containers
Validation parameters for washing containers
- Purity of the purified water
- Residence time of the object in the water bath with ultrasound
- Temperature of the water bath
- Quantity of splash water
- Spray pressure of the water in object (1 to 3 bar)
- Run-off time/remaining amount of water after blowing out with compressed air (approx. 1.5 bar)
- Number of cycles
The effectiveness of the procedure can be determined by spiking with endotoxins followed by endotoxin reduction, and by deliberate impurification of objects with standard particles (for example, 20 mm standard particles as used for testing particle measuring devices). It is important to remember that the endotoxin reduction will be disproportionately more difficult, since quantities of endotoxin applied to the glass surface structures adhere much more strongly to the surface. A 2-log reduction is normal. When rinsing particles from the surface, the quantities of rinsing agent are less significant. The impact velocity of the rinsing agent and the frequency of repetition of the process are more important factors.
For example: If 99 % of the particles present are rinsed out in one rinse procedure, three rinse procedures will cause a 6 log reduction. This means that more than three cycles will not make a significant difference to particle reduction, but will in the case of endotoxin reduction. In the latter process, the spray pressures and hence also the "penetration depth" into the surface structures are more important. However, these functions are limited by the design of the washing machine, its time settings (residence time of objects in the spray phase), and the output of washed objects per hour.
The final rinse with WFI has a particularly important effect. This stage must ensure that the internal surface quality of the objects matches with the specification of the WFI. Blowing the objects out with filtered compressed air ensures that only a small amount of residual WFI remains in the container (10 to 150 mg), and that any substances contained in this water can be precipitated on the internal surface during the sterilisation process in the hot air tunnel.
12.D.3.4 Ready to fill
In general, these are ampoules or radiation-sterilised plastic containers in sterile packaging which, after passing through an air lock into cleanliness grade B, can be passed to filling machines with LF or clean benches where they are filled with solution. This method of production is suitable if investments for larger machine systems are not feasible and qualification, process validation, and monitoring are too complex given a small number of items.
Stoppers are supplied by the manufacturers in plastic bags as a mass product with several hundred and up to a thousand items per bag. After loading into the washing machine, washing and sterilisation in the washing machine, the stoppers are automatically or semi-automatically ejected into stainless steel transport containers, which are then transported to the capping machine. Here they are mounted onto the pipe connections of the capping machine under LF. The objects can also be output in sterilised transport bags, which are subsequently heat-sealed and later emptied into the transport systems (propellant vessels) of the capping machine.
Stoppers that are supplied by the manufacturer in sterilisation bags "ready to use" must be sterilised in the steam steriliser, removed under grade B conditions, and then loaded into the transport system of the capping machine.
Stoppers that are used for sterilisable final containers, and therefore do not have to be sterile to begin with, should be stored in a cool place until needed. The microbiological load over the planned storage period must be validated.
During processing of the washing process, dry heat sterilisation, and filling stages, glass containers are transported through the compact lines on transport racks, conveyor belts, and helical conveyors. At the end of the process, the objects are transferred to stainless steel or plastic magazines. In these magazines, they can be sterilised and forwarded for visual control.
The above section describes the manufacture, material properties, and delivery packaging of the final containers and their treatment in the washing process. The processes and performance of the washing machines are described, together with the microbiological and particulate values that should be achieved in the washed containers.