Bioburden aseptic processes

Where terminal processing is not possible, the justification for alternative sterilization methods will be included in the EPAR, or at least a statement to the effect that sterile filtration/aseptic processing will be used. Presterilization bioburden issues that arose during the assessment will be included in the EPAR. 

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. 

Product behavior for a sterile product in manufacturing is also influenced by the conditions imparted due to requirements for aseptic processing. Materials prepared under laboratory conditions in a development environment are typically processed differently than in a manufacturing environment. For example, the level of cleanliness and bioburden are different. Product attributes, such as the nucleation and crystal growth of ice, would occur at different temperatures and rates. This has an influence on product behavior during processing and finished product attributes, as discussed earlier. 

Blow-fill technology is an aseptic process whereby the container is formed from thermoplastic granules, filled with sterile solution and sealed, all within one automatic operation. The bulk solution should have a low bioburden and is delivered to the machine through a filling system that has been previously sanitized and steam sterilized in situ. Concern has been expressed that the machine itself may generate particles. The plastic granules are composed usually of polyethylene, polypropylene or one of their copolymers and are heat extruded at 200°C into a tube. The two halves of a mould close around this tube and seal the base. The required quantity of sterile fluid is filled into the container, which is then sealed. Products packed in this way include intravenous solutions, and small volume parenteral, ophthalmic and nebulizer solutions. The... 

The need for higher standards of cleanliness and hygiene has already been mentioned. Since the safety factors for aseptic processes and terminal sterilisation processes rely on a low initial bioburden, attempts will continue to minimise contamination. Packaging manufacturers of materials, components and containers will therefore slowly adopt GMP procedures currently found as part of the Orange Guide in order to lower both bioburden and particulates. Cleanliness and improved hygiene are an order of the day, in terms of facilities, procedures and training. 

For concepts relating to sterility assurance and bioburden controls on the manufacture of sterile topicals, see the Guideline on Sterile Drug Products Produced by Aseptic Processing. 

The impact of the proposal may reopen a debate on the way in which SALs appear to be applied to aseptic processing. The origins of the SAL concept lie in terminal sterilization and rest heavily on the extrapolated effects of uniform sterilization treatments to populations of contaminants defined in terms of resistance and of numbers of contaminants (biobuiden). The process of aseptic manufacture is a process of contamination control the frequency of occurrence of a contaminated item within a population of aseptically filled items is a measure of bioburden, not a measure of the SAL. The SAL is the probability of those contaminants surviving, and this is a function of the types of contaminants and the formulation of the product. Formulations can be made to be antimicrobial. In principle this is no different from chemical sterilization. 

In an aseptic process, membrane filtration is the final step before filling. During the production of a terminally sterilised product membrane filtration is applied to reduce the bioburden. 

Justifications for the use of nonstandard (i.e., nonpreferred or nonpharmacopeial) methods of sterilization may include the heat instability of the active ingredient or an essential excipient. The choice of a method based on filtration through a microbial retentive filter and/or aseptic assembly should be justified, and the appropriate in process controls (including bioburden controls on active ingredients, excipients, bulk solutions, process time constraints etc) discussed in detail in the application. Commercial considerations should not form part of the argument for the application of a nonstandard sterilization process. The highest possible sterility assurance level should be achieved. 

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. 

Components of parenteral solutions (active substances, excipients, intermediates and packaging material) should be routinely tested for bioburden and bacterial endotoxin level to ensure they are not adding an excessive microbial load. Bioburden is usually determined on the unfiltered bulk solution. Testing of filtered bulk parenteral solution either before or after filling into the final container may be done by comparison to the previously tested unfiltered bulk solution. Initial bioburden and endotoxin monitoring should be conducted to establish appropriately designed and sized terminal sterilisation methods such as filtration/aseptic filling or terminal heat treatment (see Sects. 30.5 and 30.6). Bioburden is also used as a parameter to evaluate process control. 

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