Bioburden products

Finally, filtration should be mentioned as a means of producing sterile products or gases. In the case of aqueous-based liquids (of low viscosity), terminal filtration usually employs a special fdter of 0.2 Pm (or minimum 0.22 Pm) pore size. Although a single filter can achieve effective sterility, there is a general trend towards a two fdter process, i.e. 0.45 Pm then 0.22 Pm, where applicable. In the case of more viscous products, filtration may need an increase in temperature (which usually reduces the viscosity) and/or additional pressure. Filtration techniques generally assume that the product can be produced with low bioburden products. 

Filter Selection. A variety of product- and process-related factors govern filter selection. Considerations include the characteristics of the fluid to be filtered, ie, its chemical composition and compatibiHty with the filtration system (inclusive of the membrane, filter hardware, piping, etc), the level of bioburden present, specifications on effluent quaHty, the volume of product to be filtered, flow rate, and temperature. 

Industrial sterilization cycles tend to vary considerably, not only from manufacturer to manufacturer, but often from product type to product type, depending on the bioburden present on a given load. Chemical indicators have historically been used only to differentiate between sterilized and nonsterilized packages. More recent developments have resulted in the availability of chemical dosimeters of sufficient accuracy to permit their appHcation either as total monitors or as critical detectors of specific parameters. 

Dry-heat sterilization is generally conducted at 160—170°C for >2 h. Specific exposures are dictated by the bioburden concentration and the temperature tolerance of the products under sterilization. At considerably higher temperatures, the required exposure times are much shorter. The effectiveness of any cycle type must be tested. For dry-heat sterilization, forced-air-type ovens are usually specified for better temperature distribution. Temperature-recording devices are recommended. 

Most manufacturers perform periodie tests on their products for total microbial bioburden and for the presence of known problem mieroorganisms, to be used for in-house eonfirmahon of the eonhnuing efFieiency of their GPMP systems, rather than as conventional end-produet eonformance tests. Fluetuation in values, or the appearanee of speeific and unusual species, can warn of defects in procedure and impending problems. 

A typical ETO sterilization cycle is shown in Fig. 10. As discussed at the beginning of this section, it is important to determine and monitor the bioburden level of the product entering the sterilizer. Also, the load configuration in the sterilizer is important in achieving uniform and reliable sterilization. Unfortunately, commercially available biological indicators used in ETO sterilization are often unreliable. Hopefully, progress will be made in this field in the years ahead. 

For sterile products, particular attention should be paid to the choice of an appropriate method of sterilization. Wherever possible a terminal sterilization process should be applied to the product in its final container-closure system, as suggested in the Ph Eur. The preferred options include steam sterilization, dry heat sterilization, and irradiation using the Ph Eur listed conditions (saturated steam at 121°C for 15 minutes dry heat at 160°C for 120 minutes irradiation with an absorbed dose of not less than 25 kGy). Where these cannot be used, the application must include justification for the alternative procedure adopted on the understanding that the highest achievable sterility assurance level should be achieved in conjunction with the lowest practicable level of presterilization bioburden. There is guidance in the form of decision trees as to the preferred options for sterilization method to be applied ... 

Despite rigorous implementation of GMP, most biopharmaceutical preparations will be contaminated with low levels of Gram-negative bacteria at some stage of manufacture. These bacteria shed endotoxin into the product stream, which is not removed during subsequent bacterial filtration steps. This is one of many reasons why GMP dictates that the level of bioburden in the product stream should be minimized at all stages of manufacture. 

An environment should have appropriate controls for temperature, pressure, and relative humidity. For aseptic production, cleanroom conditions monitored for particles and bioburden contamination are necessary. Equipment must be validated and maintained with current calibration. Processes must be developed and validated to ensure the production of pure and consistent product. 

As with traditional aseptic filling, in order to comply with pharmaceutical GMP, it is important to minimize contamination at all stages of manufacture. Raw materials should be of a high quality and tested for microbial contamination. Water used for product manufacture should be of low bioburden and high purity (preferably water-for-injection quality, although this requirement is dependent upon the nature of the product being manufactured). 

Coolant systems are an integral part of container formation and serve to cool the molds and, if applicable, the parison clamp assembly. Coolant, although not in direct contact with product pathways, is in close proximity to the containers, and maintenance should be carried out to prevent leakage. Coolant systems are prone to microbiological contamination and should be routinely treated to keep the bioburden imder eontrol. They should be regularly sampled and tested for bioburden to ensure continuous compliance to a predefined specification. 

To establish a microbial-limit testing history, all development, clinical, scale-up and process validation batches of new nonsterile dosage forms would be tested to verify that the pharmaceutical ingredients, manufacturing process, and packaging does not contribute to the bioburden of the product. After the testing history has been... 

For the largest batch size of each product three times 4. Microbial Effectiveness (Bioburden)... 

The product bioburden must comply with the microbial retention capacity of the filter. 

This document contains information related to the liquid aseptic fill operation used in the manufacture of (product name), USP, at ABC Pharmaceutical Industries located at (provide postal address). Additional information to support the liquid aseptic filling validation includes but is not limited to environmental monitoring and controls, as well as product-specific testing such as bioburden and sterility testing. The main subsections are ... 

ABC Pharmaceutical Industries routinely monitors the microbial content of the air, inanimate surfaces, personnel, water systems, and product component bioburden. Microbiological monitoring of these areas generally reflects on the efficiency of cleaning and sanitization procedures and employee practices. Continuous environmental monitoring provides the assurance that product is produced by a controlled process that will maximize the sterility and quality of the manufactured sterile product. 

Product component bioburden. Endotoxin analysis involves testing twenty (20) pieces. Twenty (20) vials or stoppers are filled with or immersed in WEI, mixed and sonicated. Duplicate 0.1 mL aliquots are removed and tested for endotoxin per the USP <85> Bacterial Endotoxins Test. 

Bioburden testing is performed on components prior to steam sterilization as verification that the sterilization parameters are sufficient for sterilization of components. The method for determining the bioburden level of components is included in the manufacturing site standard test method. For product component bioburden summary, refer to (provide reference attachment number). 

Incubation conditions shall be suitable for recovery of bioburden and environmental isolates at 20 to 35°C. Microbiology department shall provide a rationale for the selection of their specihc incubation conditions according to the trend analysis of area environmental control and presterilization bioburden isolates. The temperature chosen shall be based upon its ability to recover microorganisms normally found environmentally or in the product bioburden. This same panel of microorganisms shall be used in growth testing the media-hlled containers. 

Section Val. 1900 includes four aseptic processes associated with monitoring and qualification programs covering determination of components bioburden before sterilization sterility test failure investigation, bacterial endotoxin determination in WFI, in-process finished product, and monitoring the bioburden, spore bioburden, and endotoxin present on stoppers and unprocessed vials. 

Microbial Bioburden Control during Shelf Life of Pharmaceutical Products... 

Excipients Council (IPEC) [10] (excipients), and the USP [11] have also published GMP guidelines. These guidelines require manufacture of pharmaceutical products with acceptable microbial bioburden and free of objectionable microorganisms. 

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