The need to qualify an autoclave and validate the sterilization process is a result of various laws and regulations. Even if the terms qualification and validation are usually mentioned in the same sentence or even used synonymously, different statements and approaches are hidden behind them.
The need to qualify an autoclave and validate the sterilization process is set out in the German Medicinal Products Act, the Medical Devices Act, the Chemicals Act and the Biological Substances and Genetic Engineering Protection Ordinance, among others. These laws and regulations sometimes refer to directives, resolutions or decisions by the Commission, guidelines and standards. References from legally binding EU regulations to legally non-binding standards or guidelines such as the EU GxP guidelines for
These are given a law-like character and compliance with them is checked and regularly monitored by government agencies. The aim is to ensure and guarantee a high and, above all, uniform quality standard.
According to the EU GLP guidelines, systems and processes that are directly involved in the manufacturing process for product groups such as medicinal products, active ingredients, cosmetics, food, animal feed and medical devices and therefore have an influence on product quality must be qualified and validated. The requirements of the guideline on the principles of good laboratory practice are aimed at laboratories that carry out non-clinical studies on test objects such as medicinal products, plant protection products, biocides, cosmetic products, veterinary medicinal products, food additives, feed additives and industrial chemicals. Equipment and processes used to inactivate human sample materials (body fluids, tissue, cell cultures, etc.), microorganisms, cell cultures, endoparasites - including their genetically modified forms - are also covered by this.
It is a requirement of the principles of good laboratory practice that equipment, including validated computerized systems, used to obtain, record and reproduce data and to control the environmental conditions relevant to the test must be of suitable design and adequate performance. If your autoclave is directly involved in studies on the aforementioned product groups, its suitability in terms of design and performance must be demonstrated. In detail, the supervising authorities will define the requirements for the qualification and validation process and documentation by specifying standards, guidelines, etc. or, if necessary, refer to standards, as standardization is also subject to certain limits.
As the operator of an autoclave that is integrated into your manufacturing process - or as the operator of a laboratory - you are responsible for your manufacturing process and for the results and conclusions of your study. Qualification and validation is often carried out with the help of an appropriately qualified service provider. As only you can define the product-specific requirements for your process, close cooperation between your specialist departments, the qualifier/validator and the autoclave manufacturer is necessary.
Even if the terms qualification and validation are usually mentioned in the same sentence or even used synonymously, they actually refer to different statements and approaches. What the two terms have in common is that directive-compliant documents containing the definition of the individual tests and the documentation of the test results must be created. In many cases, the written qualification/validation plan also includes protocols that are used to document the test results during execution.
Qualification: The purpose of a system qualification is to prove that a system with the technology used is suitable for the intended task, works perfectly and delivers results that meet the requirements. The main focus here is therefore on the system (the autoclave) and its correct functioning.
Validation: The objective of process validation is to prove that the process is effective and reproducibly delivers a product (result) that meets the specified quality requirements. The main focus here is therefore on the process itself and the proof of compliance with the acceptance criteria to be defined by the operator of the system.
Process qualification is often a process that takes place within a plant, which explains the link between the terms.
The first qualification stage of an autoclave begins the moment you formulate and document your requirements for the device to be purchased. This is where you create your User Requirement Specification (URS), i.e. the requirements that are placed on a device and which must be fulfilled. Autoclaves from many manufacturers can be equipped with options that influence process accuracy or process speed, for example. If certain options are not taken into account in the URS depending on the processes to be carried out, and if these are not added to the device accordingly, this can make successful qualification and validation significantly more difficult or even completely impossible at a later stage. Even at this early stage, future operators should therefore specify exactly what the autoclave is to be used for, what requirements are placed on the processes and which standards and guidelines must be complied with.
The scope of the URS will vary greatly depending on the complexity of the system or autoclave. Autoclave suppliers will submit a quotation on this basis and the specifications and requirements will be drawn up in consultation between the operator and manufacturer. The compliance check is an elementary component of the first qualification stage - the design qualification (DQ). After successful DQ, the device is manufactured by the manufacturer according to the agreed specifications. The preparation of the documents required for the subsequent IQ, OQ and PQ steps (validation plan) can now begin in parallel (either internally, with the manufacturer or with a separate service provider). These documents form the basis for carrying out the IQ, OQ and PQ and specify the inspections and tests to be carried out as well as their parameters and acceptance criteria. Detailed documentation is necessary in order to be able to prove that all checks and tests have been carried out successfully.
Once the design qualification has been successfully completed and the appliance has been delivered, the next qualification stage of the autoclave can begin on site - the installation qualification (IQ). Here, the suitability of the installation site, the physical characteristics of the delivered autoclave and the completeness of the documentation pertaining to the device are checked and documented in the qualification documents. Documentation generally includes the operating instructions, maintenance, cleaning and calibration instructions, as well as material certificates and data sheets for individual installed components.
If this qualification stage has also been successfully completed, or if any deviations identified have been assessed on the basis of a risk analysis and appropriate measures have been initiated to rectify them, the functional qualification (OQ) of the system can begin.
Here, proof is provided that the devices, equipment, utilities or systems comply with the operator's requirements and specifications that were defined during the design qualification. Tests are carried out to prove that the device works as planned. This includes calibration as well as the simulation of error, fault and shutdown conditions of the device. This procedure serves as documented proof that the autoclave correctly detects errors that could be relevant to safety or affect the quality of the product.
The performance of sterilization runs of the autoclave without product inserted is also part of the functional qualification. Temperature sensors and a pressure sensor are installed in the autoclave, which use a data logger to measure pressure and temperature independently of the autoclave control system. The temperature and pressure values determined in this way can thus be checked against the values determined via the autoclave control system. In addition, bioindicators based on Bacillus stearothermophilus are introduced into the autoclave to prove the biological effectiveness of the sterilization process. The aim is to provide documented proof that a system or device, without product, is suitable for its intended use.
Once the autoclave has been proven to function correctly without product, the performance of the device is checked in accordance with the specifications of the validation plan defined in advance, with the aim of demonstrating that the specified process requirements are adequately met under real conditions (with product). It should be noted that the temperature distribution depends on the product to be sterilized and therefore a separate PQ test must be carried out for each load configuration. For this purpose, load patterns are defined which should be representative of the loads to be expected in everyday operation. This is often done according to the following scheme:
However, the worst-case load must always be checked, e.g. in relation to the load quantity. Other parameters may have to be taken into account if they could have an influence on the result of the sterilization process.
As in the OQ, the sterilization process is checked by temperature and pressure sensors that record the relevant data independently of the autoclave control system using a data logger. In addition, the biological effectiveness of the sterilization process is also verified by reference indicators based on Bacillus sterothermophilus. In the PQ, unlike in the OQ, the temperature sensors and also the biological indicators are placed in the product to be tested (load sample) in order to provide evidence of the sterilizing effectiveness in the product. It is important that the temperature sensors and also the bioindicators are placed in the areas of the product where it is expected that a sterilizing effect will be most difficult to achieve. The aim is to provide documented proof that a process reproducibly delivers the expected result, taking the product into account.
When carrying out OQ and PQ, the number of temperature measuring points within the usable space should comply with the recommendations from relevant standards such as EN 556 or the GxP guidelines, as any deviation from these will probably lead to queries during an inspection. For example, 12 temperature measuring points should be provided per 1m3 of sterilization space . A bioindicator based on Bacillus stearothermophilus is placed at each temperature measurement point.
Sterility assurance level
The EN 556 standard also provides information on the question of when a product can be described as sterile or when a sterilization process is considered reproducible, i.e. always delivers the same result (a sterile product). The so-called Sterility Assurance Level (SAL) is defined here. The SAL is based on a theoretical population of, for example, 100,000 (105) microorganisms (colony forming units - CFU).
Bacillus stearothermophilus is used as a reference indicator (bioindicator) for testing steam sterilization processes. The SAL now requires that, depending on the product to be sterilized, the highest possible probability must be achieved that all microorganisms are actually killed and therefore all products are actually sterile. This highest possible probability is considered to be proven if a SAL value of 10-6 is achieved. This means that the probability that a product is still non-sterile after the sterilization process is 1 : 1,000,000.
If all qualification stages and the process validation(s) have been successfully completed, the operator must define an interval for re-validation. It is advisable to coordinate this with the autoclave manufacturer, as it makes sense to combine the re-validation with the necessary recurring calibration of the device sensors.
Care should be taken when changing process parameters. These include, for example
If the changes listed above occur, their influence on the validated overall process must be checked. If the change is expected to have an impact on the overall process, the impact must be determined, evaluated and documented as part of a re-validation. This may result in necessary adjustments to the overall process so that it can continue to comply with the parameters defined before the change.
As changes sometimes occur gradually, i.e. are difficult or even impossible to notice, a re-validation should always be carried out at fixed intervals. An interval of one year has proven effective here. For particularly critical processes, however, the interval for re-validation can also be set at shorter intervals.
This article was published in the LABO Magazine 05/2018.
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