2024.02.28
The effectiveness of irradiation sterilization depends on the quantity and type of biological load on the product. Therefore, when establishing the sterilization dose, it is necessary to determine the biological load, which needs to be determined regularly on a daily basis, and biological load measurement should also be conducted during dose review. Once there is a change in the quantity or type of biological load, it may lead to the failure of sterilization dose audit, affecting the effectiveness of the original sterilization dose setting. Therefore, in daily management, it is necessary to control various factors that may affect the biological load, such as materials, production environment, production process, product structure, composition, etc. When these factors change, it is necessary to carefully evaluate their impact on the biological load on the product.
The standards related to bioburden mainly include the following:
GB/T 19973.1-2015 idt ISO 11737-1:2006 Microbiological Methods for Sterilization of Medical Devices Part 1: Determination of Total Microbial Count on Products
GB/T 19973.2-2018 idt ISO 11737-2:2009 Microbiological Methods for Sterilization of Medical Devices Part 1: Aseptic Tests for Definition, Confirmation, and Maintenance of Sterilization Processes
Chinese pharmacopoeia
YY/T 1737-2020 Analysis Method for Bioburden Control Level of Medical Devices
The important influencing factors on the determination of biological load quantity mainly include the following aspects:
1）SIP
2) Bioburden collection technology
3) Bioburden cultivation technology
Although the standards related to irradiation sterilization mention the use of SIP, it should be noted that using SIP is only a last resort. SIP can only be used when the volume of the product exceeds the laboratory processing capacity. Considering that microorganisms are not evenly distributed on the product; For instruments with complex structures, the difficulty of collecting microorganisms from different parts may vary; Some products may be composed of liquid, soluble materials, and insoluble materials, which can make it difficult to determine a reasonable SIP value. Therefore, although the 19973 standard provides some basis for SIP calculations, it is clear that these basis cannot guarantee applicability to all listed products. It is basically impossible to obtain the natural attachment of microorganisms on the product in advance, and it is difficult, even impossible, to determine the rationality of SIP through actual verification. Therefore, it is advisable to avoid using SIP as it may lead to unforeseeable consequences if an unreasonable SIP is used.
Bioburden collection technology is another important factor that affects the results of bioburden measurement. The first decision to use bioburden collection technology is based on the form of the product. For liquid or soluble medical devices or their components, membrane filtration can be directly used, but the impact of residual substances such as fibers or particles in the liquid or after dissolution on filtration may need to be considered. However, for insoluble medical devices, without considering the impact of SIP, their bioburden measurement is only an estimate and it is impossible and unnecessary to obtain accurate results.
1) The original number of microorganisms attached to medical devices is unknown. The difference in using vaccination methods for evaluation may be significant. Therefore, it is almost impossible to evaluate whether a certain collection technology is optimal for a certain medical device product, and can only be selected based on product characteristics, experience, operational convenience, and other factors. The appendix of 19973.1 provides some commonly used acquisition techniques, such as bag peristalsis, ultrasonic washing, shaking, vortex mixing, rinsing, stirring (fragmentation), wiping, etc., and also gives some usage requirements and precautions.
2) When collecting biological loads, the use of collection techniques that may lead to microbial death or prolonged collection time that may cause microbial growth may result in a deviation between the amount of biological load obtained and the true value. However, due to the unpredictability of the original microorganisms attached to medical devices, the use of inoculation methods to evaluate recovery rates is also unreliable, and assessing the possibility of microbial death or growth caused by collection techniques has become a challenge. Of course, for some products, it may be possible to evaluate them through vaccination methods. Therefore, in most cases, the collection method and eluent can be selected based on the product characteristics according to some instructions in the Chinese Pharmacopoeia 19973, and the collection time should be minimized as much as possible to avoid microbial growth. However, when selecting collection techniques and determining optimization parameters, comparisons of optimization conditions can be made through methods such as inoculation or intentionally increasing the biological load. For example, evaluating collection parameters such as oscillation frequency, oscillation time, sequence, etc,
The bioburden cultivation technology is described in both the Chinese Pharmacopoeia in 1997 and the Chinese Pharmacopoeia, and can be directly selected.
Considering these factors, as well as the use of correction factors mentioned in 18280. Correction factor is an estimation method for product bioburden, which has applications in establishing sterilization dose. However, different methods have different requirements for correction factors.
In 18280, the use of correction factors was described as follows:
——Method 1: Average biological load ≥ 1.0, multiple production batches, correction factors can be used; Average biological load of 0.1-0.9, multiple production batches, using correction factors;
——VDmax25, average biological load ≤ 1000, multiple production batches, using correction factors;
——VDmax15, average biological load ≤ 1.5, multiple production batches, using correction factors;
For method 1 with an average biological load ≥ 1.0 and multiple production batches, it is stated in 18280 that "using method 1 does not require this correction factor, as failure to use this correction factor may result in an underestimation of biological load. Failure to apply the correction factor may lead to the risk of validation dose failure." This means that even if the biological load is underestimated, as long as the validation dose passes, the sterilization dose is safe and reliable.
For Method 1 with an average bioburden of 0.1-0.9 and multiple production batches, if no correction factor is used, the actual bioburden may be ≥ 1.0, which requires the application of another program. Whether to use correction factors may affect the selected program, in which case correction factors need to be used. Of course, if it can be determined that the actual average biological load cannot be higher than 0.9, then not using correction factors is only a risk of dose failure, and not using correction factors is not a problem.
For VDmax25, as long as the validation dose is successful, its sterilization dose is 25kGy. The correction factor has no effect on the selection of sterilization dose. However, if a correction factor is used and the average biological load exceeds 1000, but no correction factor is used and the average biological load does not reach 1000, this will affect the applicability of the sterilization dose establishment method. Therefore, in the case where the actual average biological load can be ensured to be less than 1000, not using correction factors will only bring the risk of failed validation dose, and will not bring the risk of insufficient sterilization dose.
For VDmax15, with an average bioburden of ≤ 1.5 and multiple production batches, if no correction factor is used, the actual bioburden may be greater than 1.5, which may lead to errors in selecting the method for establishing sterilization dosage. Of course, if it can be determined that the actual average biological load cannot exceed 0.9, not using correction factors will only bring the risk of failed validation dose, and will not bring the risk of insufficient sterilization dose.
The true function of the correction factor is mainly in the selection of the method for establishing the sterilization dose, and it has almost no impact on the effectiveness of the sterilization dose. Of course, the correct selection of the method for establishing sterilization dosage is also an important factor in the effectiveness of sterilization dosage. It is difficult to say whether the effectiveness of sterilization dosage can be guaranteed if the establishment method is incorrect.