Sterilizing and filtering process applied to preparation of isiomerazole

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a sterilization and filtration process applied to preparation of isimerazole. Comprising the following steps: placing the preparation in sterilization equipment, and utilizing saturated steam, a steam-air mixture, a steam-air-water mixture and superheated water to denature protein and nucleic acid in microbial thalli so as to kill microorganisms.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and in particular relates to a sterilization filtration process used in the preparation of esomeprazole. Background Art

[0002] Esomeprazole is the S-isomer of omeprazole. It reduces gastric acid secretion through specific proton pump inhibition. The R-isomer and S-isomer of omeprazole have similar pharmacodynamic properties. Esomeprazole is a weakly alkaline drug. It is concentrated and converted into an active form in the high acid environment of the acid secretory microtubules of parietal cells, thereby inhibiting the H+ / K+-ATPase (proton pump) in this area, and inhibiting both basal gastric acid secretion and gastric acid secretion after stimulation.

[0003] Freeze-drying technology refers to a technology that directly sublimates water from solid to gas in a vacuum environment below zero degrees, extracting the moisture in the product and thus completely preserving the activity of biological components.

[0004] Esomeprazole is a lyophilized powder for injection. The production process mainly includes drug solution preparation, sterilization filtration, and freeze drying. The key steps include the pH range of the drug solution, the temperature and light stability of the drug solution, filtration, freeze drying, etc.

[0005] Sterile drugs refer to preparations and APIs that have sterility inspection items listed in the statutory drug standards, generally including injections, sterile APIs and eye drops, etc. Strictly speaking, sterile drugs should not contain any living microorganisms, but due to the limitations of current testing methods, the concept of absolute sterility cannot be applied to the sterility evaluation of the entire batch of products. Therefore, the concept of "sterility" currently used is "sterility" in a probabilistic sense. Summary of the invention

[0006] The object of the present invention is to provide a sterilization filtration process for the preparation of esomeprazole, which is conducive to large-scale mass production and has stable product quality and high qualitative properties.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A sterilization filtration process for the preparation of esomeprazole includes placing the preparation in a sterilization device and using saturated steam, steam-air mixture, steam-air-water mixture, and superheated water to denature proteins and nucleic acids in microbial cells to kill the microorganisms.

[0009] The process also includes a step of filtering through a polyethersulfone filter membrane having a pore size ranging from 0.03 to 5.0 μm.

[0010] Compared with the prior art, the present invention has the following beneficial effects:

[0011] The sterilization temperature and time of moist heat sterilization process usually affect the killing effect of microorganisms, especially those with greater tolerance. The overkill method assumes that the microbial load and tolerance are higher than the actual situation. In theory, it can completely kill microorganisms, which is sufficient to meet the requirements of sterility assurance level. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 This is the process flow chart for injection sterilization. DETAILED DESCRIPTION

[0013] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0014] Example

[0015] A sterilization filtration process for the preparation of esomeprazole includes placing the preparation in a sterilization device and using saturated steam, steam-air mixture, steam-air-water mixture, and superheated water to denature proteins and nucleic acids in microbial cells to kill the microorganisms.

[0016] The process also includes a step of filtering through a polyethersulfone filter membrane having a pore size ranging from 0.03 to 5.0 μm.

[0017] Under process conditions, sterilizing grade filters can retain ≥107 CFU (colony forming unit) of Brevundimonas diminuta per square centimeter of effective filtration area. Sterilizing filtration processes usually use 0.22 μm sterilizing grade filters.

[0018] Measures should be taken as much as possible to reduce the risk of sterilization filtration, for example: ① A second sterilized sterilization filter should be installed, and the final sterilization filter should be as close to the filling point as possible; ② Since the probability of microorganisms passing through the sterilization filter increases with the increase in the number of microorganisms in the liquid to be filtered, the microbial load of the liquid to be filtered is generally less than or equal to 10 cfu / 100 ml before the final sterilization filtration; ③ The process time limits such as the storage time from preparation of the liquid to filtration, the time of the liquid filtration operation, and the time of placement from filtration to filling should be determined through research.

[0019] The drug and / or process conditions themselves may affect the viability of the challenge microorganism. Therefore, before conducting a bacterial retention test, it is necessary to confirm the survival of the challenge microorganism in the drug under process conditions (survival test / activity test) to determine a reasonable bacterial challenge method. For non-bactericidal / non-bacteriostatic drug solutions, directly inoculating the test microorganism in the drug solution is the preferred method for testing the bacterial retention capacity of sterilizing-grade filters (filter membranes); for antibacterial / bactericidal drug solutions, the filter (filter membrane) can be pre-treated by modifying the process (such as adjusting the temperature) or modifying the test solution formula (adjusting the pH value, removing the bactericidal component, or using an alternative solution for the product) before conducting a bacterial challenge test. If an alternative solution is used for the test, reasonable data and explanations need to be provided. For products of the same family, that is, products with the same components but different concentrations, the challenge limit concentration method can be used for verification, and the intermediate concentration can be accepted as an alternative.

[0020] Filtration temperature, filtration time, filtration batch and pressure difference or flow rate will affect the results of the bacterial retention test. It is recommended to conduct a thorough evaluation of the actual production filtration process, including solvent properties (such as aqueous, acid, alkaline, organic), filtration time, process pressure difference, process flow rate, process temperature, filtration batch and filtration system design specifications, so as to reasonably design the microbial retention test conditions. If the test microorganisms are detected downstream of the filter in the bacterial retention validation study, an investigation should be conducted. If the investigation confirms that the test microorganisms can penetrate the filter that meets the integrity test standards, then the suitability of this filter under these working conditions should be reconsidered.

[0021] Integrity testing runs through bacterial retention tests and chemical compatibility tests. In addition, integrity testing is also involved in the validation of three consecutive batches of drug production processes and routine production processes. The wetting medium (including standard media such as water and alcohol solutions or drug solutions) for the integrity test of the filter after use should be clearly defined. If the wetting medium used is a drug solution, the product-related integrity standard should be verified to support the determination of the standard. For redundant filtration, the main filter should be tested for integrity after use. If the integrity test of the main filter passes, the redundant filter does not need to be tested for integrity; if the integrity test of the main filter fails, the redundant filter needs to be tested for integrity. For sterilization units that have been verified to require a series (two or more) of sterilizing-grade filters, all must pass the integrity test after use.

[0022] Reuse of filters is not recommended for pharmaceutical processes. If reuse occurs in actual work, a full risk assessment should be conducted, including bacterial penetration, filter integrity defects, changes in extractables, the applicability of the cleaning method to the cleaning of components in the product, the impact of product residues (or derivatives of components after sterilization) on the quality risk of the next batch of products, premature filter clogging, performance changes caused by aging of filter components, etc., and sufficient verification and data support should be provided.

[0023] Sterile filtration is usually designed at the front end of the filling of sterile preparations produced by terminal sterilization process, or at the front end of the sterilization filtration process of sterile preparations produced by non-terminal sterilization process. Filters with pore sizes of 0.45μm or 0.22μm (or below) are usually used. Validation for sterilization filtration should include chemical compatibility, extractables / leachables and adsorption tests.

Claims

1. A sterilizing filtration process for the preparation of esomeprazole, characterized in that The method comprises the steps of placing the preparation in a sterilizing device and using saturated steam, steam-air mixture, steam-air-water mixture, or superheated water to denature the proteins and nucleic acids in the microbial cells to kill the microorganisms.

2. The sterilizing filtration process for preparing esomeprazole according to claim 1, characterized in that The process also includes a step of filtering through a polyethersulfone filter membrane having a pore size ranging from 0.03 to 5.0 μm.

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