Washing And Sterilizing Pharmaceutical Containers
By Claudio Sechini, Product Manager, Libra Pharmaceutical Technologies
In the pharmaceutical industry, containers intended for sterile or non-sterile preparations are processed differently according to the material of which the container is made and the type of product to be prepared. Containers coming from suppliers, even those manufactured according to high quality standards, may be contaminated by various particles which need to be removed before the containers are filled. For years, Libra Pharmaceutical Technologies' specialty has been research in and construction of container decontamination systems ranging from simple blowers to washing machines and sterilization tunnels.
In the production of pharmaceuticals, particular attention must be given to preparation of injectible drugs. These preparations must satisfy a number of prerequisites, namely they must be pure, sterile and non-pyrogenic, conditions achieved by means of washing machines and sterilization tunnels. Effective washing is imperative, since parenteral products injected into humans bypass natural contaminant barriers and mucosa.
Clearly, then, washing is as essential in processing injectibles as the itinerary subsequently experienced by the container. Glass containers used for injectible liquids may be contaminated by such particles such as glass, rubber, fiber, or metal, as well as by bacteria, alkaline oxides, or calcium oxides. These contaminants are classified as "available" or "not available." The former are those removable by simple dilution, that is by simple contact with water. The latter are those which require mechanical action to be removed. Non-available particles are normally present in bottles made out of tube glass and include alkaline and calcium oxides, materials are generated by sublimation during glass formation. These particles can be removed by ultrasonic cleaning followed by washing. In this case, the final station includes at least a WFI unit from which the washing water is recycled to the first stations; at intermediate units sterile filtered air is blown.
Libra has always considered container decontamination to be one of the crucial steps in the processing cycle of a sterile line, so this operation is given special attention and worked out from scratch for each project.
This approach, extremely important from a technical point of view, has led to the development of 600 different washing cycles which, since they are designed process-specifically, have never failed to meet specified decontamination requirements. In machine construction, all details are designed and executed with utmost care.
For example:
- piping is designed to avoid contact between weldings and media
- circuitry has been mounted at an ideal angle of inclination for ensuring perfect drainage
- mechanical components, process areas, and fluid circuitry are kept completely separate to avoid cross-contamination
- lifting needles and all other movements have been fitted with clutch levers to ensure against bottle breakage, even when the bottles are made out of tube glass.
Libra washing machines features an exclusive discharge system for the "positive horizontal ejection" of containers from the baskets, which ensures against any risk of cross--contamination from water drops which may fall back into the container. The discharge area is operated in such a way as to ensure first-in/first out operation from the bottle washer and, simultaneously, the offset loading of the tunnel. All this means unfailing process consistency, which translates into high production efficiency and quality.
As previously mentioned, injectibles must undergo some type of treatment to make them sterile and non-pyrogenic. Injectibles are defined as sterile when they are free of any living microorganism - pathogenic or not - which are capable of reproduction.
Products are said to be non-pyrogenic after all substances derived from the metabolic processes of microorganisms, whether pathogenic or not, or from the decayed matter of non-living microorganisms, having been inactivated. When injected into humans or animals, especially intravenously, these by-products, commonly known as "endotoxins," cause a number of pathological reactions, the most evident of which is fever. Since many products are thermostable, they can be sterilized and made non-pyrogenic by filtration and/or final autoclaving. Autoclaving, however, does not ensure inactivation of endotoxins produced by gram-negative bacteria and, moreover, sterilization of the product in the final container is not always possible. In cases where product sterilization in the final container is not practicable because of thermolability, the container must be sterilized before the product is introduced and the product must be sterilized separately by filtration.
Glass containers for injectible products are normally sterilized by means of dry ovens or sterilization tunnels. According to all surveyed pharmacopeias, ascertaining the absence of pyrogens requires the endotoxin charge to be reduced by at least 3 log. The assay may consist of the "rabbit test" or a "LAL test." Apart from differing operationally, the two tests are also different in terms of response sensitivity. Today, the LAL test is more commonly used since it is more sensitive and economical than the rabbit test. Since endotoxins are produced by the cell breaking up during sterilization, this treatment is to be considered mandatory for making products non-pyrogenic.
The reason for dwelling so long on depyrogenation is that this operation is all too often ignored or underestimated. Since depyrogenation is achieved at temperatures lower than the ones employed in the cleaning tunnel, or in any case much lower than those reached by glass, the equivalent time, called F(endo), must be calculated by the following equation:
F(endo) = SDT 10 {exp} (T-Trif / Z)
The temperature at which Escherichia coli endotoxins are inactivated, namely 250ºC, has been adopted as a reference. This temperature is referred to as Trif. The time required for reducing an endotoxin charge by 1 log is set at 5 minutes. In fact this is twice as long as is actually required. By convention, a value of 46.4ºC has been adopted for the Z parameter. This value, also defined as the lethal ratio, is the difference between the inside glass temperature and the reference temperature.
The Libra sterilization tunnel consists of three chambers: an infeed chamber, the sterilization chamber, and a cooling chamber. The infeed chamber is fitted with a fan, which pulls conditioned air through a prefilter and a working filter. The air directed to the bottles is then aspirated symmetrically from beneath the belt and expelled as it is saturated with moisture. The sterilization zone recycles 80% of the air, while the remaining 20% is made up by an additional fan. The recycled air is heated by means of electric resistances and conveyed above the filters, after which it is directed to the bottles, thus bringing them to a high temperature. After entering the bottles, air is symmetrically aspirated out. The tunnel ensures that the air inside the hot chamber is constantly changed and kept under control. This makeup system also ensures that the pressure in the sterilization chamber is always greater than that in the adjacent chambers. The air in the cooling chamber is recycled by 90%, the remaining 10% coming from the hot chamber. The infeed and cooling chambers are connected via the duct through which the belt returns to the infeed area.
Libra tunnels feature technological characteristics, which are the result of years of study, field tests, and applied research. Some of these include:
- An exclusive "no bypass" system on the filter seals which does not require that the seals be fitted
- Make up system
- Proprietary tunnel balancing system, which permits operation under a wide range of pressure conditions so that tunnel can be run at a pressure greater or lower than or equal to that of the sterile chamber
- One system featuring all instrumentation for its calibration and validation according to even the most restrictive requirements.
It is difficult to convey in a short paper the results of years of commitment and hard work and of the investments required to develop such advanced technology. Libra's commitment to research and development is ongoing. For example, we have recently patented a novel system for tunnel sterilization. This technology solves a long-standing problem that has always accompanied the production of injectible pharmaceuticals, namely the sterility of the cooling zone.
This innovation has resulted in a long-sought objective finally becoming a reality: a sterilization tunnel capable of thoroughly sterilizing itself before sterilizing the bottles.
For more information: Claudio Sechini, Product Manager, Libra Pharmaceutical Technologies, Via Baldanzese 149, 50041 Calenzano (Firenze), Italy. Tel: +39-55-887-3220, fax: +39-55-887-9745.