Rongcheng Jingyi Oceanic Technology Company Limited , https://www.jingyifoods.cn
Q: What is the sterilization filtration process?
A: Sterilization filtration refers to the process of filtering and removing microorganisms from fluids without affecting product quality. Taking liquid filtration as an example, although the process described in the above definition has a wide and widespread application in pharmaceutical production, we need to distinguish between the following two different situations: * refers to products, intermediates or other processes. The feed liquid is unstable, and the Zui terminal sterilization method approved by the regulatory department including heat sterilization cannot be adopted, and the filtration sterilization method is adopted, and the filtrate is required to be sterile; the second is Refers to the use of filters with different precision (poresizerating), even the sterilization filter, the process fluid is filtered, and only the microbial contamination level of the filtrate is required, and there is no sterility requirement.
In the above two, the former can be understood as a narrow definition of sterilization filtration, referred to as "sterilization filtration"; while the latter is a broader concept, commonly referred to as "bioburden control filtration", The filter used in the process is called "microbial contamination level control filter" to distinguish it from the case of *. In different applications, the regulatory requirements for filters are also different.
Q: What is the risk of the sterilization filtration process?
A: On the basis of summarizing long-term pharmaceutical practices, Western medical regulatory authorities have proposed the order and principles of decision-making judgments on the basis of risk-based selection of various sterilization methods in the pharmaceutical process. The European Medicines Agency (EMA) has further summarized such decision-making principles and processes as a “decision tree†and published it as a regulatory guide. Its ideas have far-reaching implications and are widely cited by various industry guidelines and technical references. In the new Chinese GMP and Pharmacopoeia (2010 edition), the above ideas are also reflected in the terms and regulations of the sterilization method.
The above EU sterilization decision tree states that among all sterilization methods, the terminal moist heat sterilization method should be preferred, that is, the sterilization of the zui final product of the sterile drug; the excessive thermal instability of the product component cannot be used excessively. When killing the heat sterilization conditions, other sterilization methods and/or parameters that have been verified and meet the regulatory requirements for sterility assurance (SAL) should be considered; only if the product cannot tolerate the above-mentioned final sterilization conditions At the time, the combination of the sterilization filtration process and the aseptic operation is considered to carry out the production of the drug. If the product is not resistant to sterilization filtration or can not be sterilized and filtered, Zui's high-risk production process is aseptic dispensing and filling.
It can be seen that the sterilization filtration process is in a high risk position in the above decision-making process.
Q: What is the definition of a sterilizing filter?
A: At present, national regulatory agencies have a unified understanding of the definition of sterilizing filters, and are written into regulatory requirements or guidelines.
The US ASTMF-838 standard has now become the standard method for confirming and verifying the microbial retention efficiency of liquid sterilizing grade filters, that is, the effective filtration area per square centimeter challenge level reaches 107 CFU, and the challenge microorganism is Prevundimonas diminuta (ATCC 19146). In case, the filtrate is sterile filter.
Currently on the market, sterilization filters are usually marked with a 0.2μm or 0.22μm aperture accuracy, however, two points should be noted, namely: the two precisions are interchangeable, no difference; non-sterilization grade filter products Also, it is marked with an accuracy of 0.2 μm (or 0.22 μm). Therefore, it is necessary to select and judge whether or not the filter is "sterilization grade", and it is not necessary to determine whether the aperture is 0.2 μm (or 0.22 μm) or not, and it is also necessary to follow the definition in the above regulations.
Q: How to use the quality management method in the pharmaceutical production process to reduce the risk of the sterilization filtration process to meet the expected requirements of sterility assurance?
A: The use of properly validated sterilizing filters is one of the effective means of reducing the risk of this process.
As a special commodity, drugs should be produced in a highly guaranteed manner to meet all predetermined criteria. All sterilization methods used in the production of sterile drugs, such as moist heat sterilization and dry heat sterilization, should be verified in accordance with domestic and international requirements. Among them, the sterilization filtration process as a risk is much higher than the process of the heat sterilization method, and the necessity and importance of the process verification is not necessary.
Both US and EU drug registration guidelines and/or GMP regulatory guidelines require specific product validation for bacterial retention efficiency of the sterilization filtration process, ie, the sterilization filter used under specific product and set process conditions Conduct a validation study.
Q: In terms of sterility assurance, what are the verification requirements for sterilizing filters in advanced national regulations?
A: For sterilizing filters used in sterile filtration on the narrow concept, the US and EU GMP guidelines provide four requirements for sterility assurance, namely: product (process fluid) challenges The effects of microbial viability, microbial interception process validation using true products (process fluids) and "zui poor conditions", filter integrity testing and integrity detection values ​​need to be correlated with microbial cutoff validation data.
The specific meaning of these four requirements is explained in detail as follows:
Effect of Product (Process Fluid) on the Survival of Challenge Microorganisms Inoculation of test microorganisms directly in real products (process fluids) is the preferred method for process validation of microbial retention capacity of sterilizing grade filters. However, it is only feasible if the product (process fluid) is proven to have no germicidal efficacy under the process conditions, ie, the product has no effect on the viability of the challenged microorganism, otherwise an alternative method is required for the verification experiment. This is the purpose of this verification and is the reason why the regulations require this verification to be performed prior to the validation of the microbial interception process.
Process Verification of Microbial Entrapment Efficiency The purpose of this validation study was to obtain documentary evidence that under simulated process conditions, the filtration process can continue to remove a certain number of standard bacteria or related microbial contamination isolates suspended in the product (or replacement fluid). This verification needs to consider the "zui difference condition" of the actual process, and Zui greatly guarantees that in the normal production process, the sterilization filtration can reach the sterility assurance level required by the regulations. This part of the process verification is based on the fact that the filter manufacturer can provide the finished filter under standard experimental conditions using a reference fluid (such as water, lactose broth) to achieve the microbial retention efficiency of the sterilization filter. Confirmation of this part of the research data provided by the filter manufacturer is the core audit work of the pharmaceutical manufacturer when selecting the sterilization filter supplier.
According to international practice, the spiking/spikedstudy, which uses contaminants to enter the real product, can be scaled down. The same is true for this verification. Since the purpose of the study was to demonstrate the microbial retention performance of filters made of a particular membrane in a real process, the use of small test membranes is generally considered to be satisfactory.
Integrity Testing Integrity testing of a sterilizing filter refers to a physical inspection of the filter while it is wetted by the liquid. Although this test cannot be considered as a verification study, especially when the filter is wetted with a reference fluid such as water (if the actual product (liquid) is used as the wetting fluid, the integrity value and reference under such conditions need to be completed. The correlation of the integrity values ​​of the fluid (such as water) wetting, this correlation process is also a validation study), however, because the aforementioned microbial interception experiments are themselves on GMP-scale production sites and filters intended for formal production, It is destructive. Therefore, this test is an important means to establish the "identity" between the filter to be used in production and the proven filter. It is also a high-risk process for sterilization filtration in daily drug production. The core equipment used in the sterilization filter is the necessary monitoring point for quality control.
Association of Integrity Detection Values ​​with Microbial Retention Efficiency As previously stated, microbial interception verification is a destructive test and cannot be used to demonstrate the integrity of the filter to be used in production. The primary purpose of non-destructive physical integrity testing is to determine if there are defects that may jeopardize filter rejection without destroying the filter. Therefore, how to establish an integrity detection limit is a user of the filter - the pharmaceutical manufacturer - very much needs attention.
The limit for this test is that the filter manufacturer conducts a microbial challenge test on a series of filters with different integrity test values ​​until a microbial transmission of some filters is observed, according to which the filter is The process of establishing physical limits for physical integrity testing.
Therefore, if the limit set by such experiment is not used and the integrity test is not based on this limit, only the physical detection of the filter can be performed as a quality control means in the production of the drug, and the sterilization of the drug. There is no point in guaranteeing.
Q: In addition to sterility assurance considerations, is there any additional validation required for the sterilizing filter?
A: The filter is used as a production facility for direct contact with pharmaceuticals and is subject to other relevant GMP provisions. Specifically, the filter must not adversely affect the quality of the product due to reaction with the product, release of substances or adsorption. The surface of the production equipment that is in direct contact with the product shall not adversely affect the quality of the product due to reaction with the product, release of the substance or adsorption. European and American GMP and China's new GMP have raised the same or similar requirements at this point.
It should be noted that filters subject to the above regulations include both sterilizing filters and microbial contamination level control filters, as well as filters for the removal of particulate contaminants from various pharmaceutical manufacturing processes and direct contact with pharmaceuticals in accordance with the above regulatory requirements. Device.
For the relevant regulatory requirements for direct contact with pharmaceuticals, the producers and users of the filter usually need to complete the following various testing and verification studies:
The interaction between the filter and the process fluid is often one of the final processes of pharmaceutical production due to sterilization filtration. The effect of the filter on the final product of Zui should be evaluated. The investigation ranged from dissolution and precipitation, chemical compatibility and adsorption. These verifications should be carried out with real products or alternative fluids that can simulate the product.
The cleanliness of the filter should take into account particulate contamination introduced from the filter, filter hardware, filter installation and use, as each source may increase the particulate load of the product and affect product quality.
In addition to particulate matter, liquid filters may also be sources of other contamination, such as endotoxins, organic carbon or oxides. Possible sources include surfactants, wetting agents, additives in the production of plastic components, residue from manufacturing processes, and structural materials.
Through the inspection of the filtrate, the filter production process can be well monitored, which is what the filter manufacturer should perform for each batch of filters. The user of the filter needs to consider such testing when completing the initial product selection of Zui. As one of the basis for evaluating the quality of the filter, pre-flushing the filter can reduce particulate matter and pollutants in daily production use. The level can also be accomplished as part of the wetting process prior to integrity testing.
Liquid Filter Safety One of the key points in selecting filters for sterile drug sterilization filtration is to assess the safety of the filter media and filter devices to determine if they are hazardous to the drug. The filter manufacturer should provide source and toxicity data for the filter element, including the source of the component from the animal source. The filter should not release toxic substances from the filtered fluid. The filter manufacturer shall verify the safety of the filter in accordance with legal methods. Test results should generally be part of the Filter Validation Guide. The review and confirmation of this information is also one of the supplier audits that the filter user should perform.
Q: What are the differences in zui that need to be considered when sterilizing filters are verified?
A: Because the sterilizing filter is widely used in the pharmaceutical industry, the same type and system of filter products may be applied to different products, different process points and/or different process points of the same product. In the process verification according to the requirements of the regulations, in addition to the principles of process verification, the “zui difference condition†(worst case) needs to be considered in the selection of product grouping and verification conditions.
The zui difference condition in production refers to a combination of operating conditions or operating conditions close to the upper or lower limit specified in the Standard Operating Procedure (SOP), in which the product and process have a higher probability of failure than the ideal operating condition. After evaluating the process parameters and the zui difference conditions in production, the corresponding parameters and conditions are selected for process verification, which will cover various situations that may be encountered in daily production, so that the process verification representativeness is improved.
On the other hand, if it can be proved that one or several of the product families can represent the poor condition of Zui, then selecting it for process verification can represent the entire product family, reducing the workload and cost of verification.
Summary Throughout the development of domestic and international drug regulatory regulations, it is not difficult to find that under the background of globalization, drug registration and GMP regulation, "harmonization" and mutual recognition among countries and regions, It is an indisputable development trend. The European Union, the United States and Japan have taken the lead in setting up the registration and coordination mutual recognition body, ICH, in the field of drug registration. The various guidelines issued by them have already had the influence of *; the cooperative organization that is committed to the harmonization of GMP standards - PIC /S, the influence of its guidance documents has long been beyond the scope of Europe.
As a developing country with rapid economic growth, on the one hand, due to the rapid improvement of living standards, people's basic health care issues such as drug safety will soon reach a level of understanding consistent with Western developed countries, any short-sighted, neglected safety. Sexual practices will not be recognized by the market for a long time; on the other hand, many excellent Chinese pharmaceutical companies already have the desire and ability to compete in the international market, so they meet the requirements of international regulations and become international markets. *Domain threshold.
(Author: Pall Life Sciences China Dong Wei, Xie Hua, Cai Qingbo)
Risk and verification of the sterilization filtration process
With the successful promulgation of China's 2010 GMP, sterile drugs, risks and verification have once again become hot topics in the pharmaceutical industry. The risk and verification of the sterilization filtration process has also become a common concern in the industry because of the concerns of foreign regulations and the new GMP. In this paper, the three authors have answered and explained the problems of cognition in China through the innovative forms of question and answer.