Aseptic manufacture, materials

A quantity of an appropriate sterilized placebo powder is blended with sterile excipients prior to filling (if needed) in a manner similar to the production process being simulated. The medium is passed through the run as though it were an actual product batch, and all routine procedures used in manufacture of a batch are performed. Once the medium has been processed, it is held for a period of time at least equal to that for aseptically produced materials. Any aseptic manipulations performed during and at the end of the hold period should be simulated hold times and product recalculation. 

The science that underpins steam sterilization is well known and has been long established. It is the preferred method of sterilization in the pharmaceutical industry it is used for sterilization of aqueous products in a wide variety of presentations, for sterilization of equipment and porous materials required in aseptic manufacture, in microbiology laboratories for sterilizing media and other materials, and for sterilization of massive systems of vessels and pipework [steam-in-place (SIP) systems]. Numerous rules and guidelines have been published on the topic, yet steam sterilization and particularly bio-validation of steam sterilization is still a subject for controversy and debate. 

Pharmaceutical Products and Materials for Aseptic Manufacture—Sterilization Specifications... 

For pharmaceutical products and materials used in connection with aseptic manufacture, sterilization specifications apply to conditions of temperature and time, or Fq, or combinations of Fq, temperature and time to which the contaminating micro-organisms themselves must be exposed over the hold period of the sterilization process. In practice, this means actually within aqueous products, on the surfaces of rubber stoppers or metal machine parts, or within the folds of cartridge filters, etc. 

Are they intended to apply within the media as are the sterilization specifications for pharmaceutical products and materials for aseptic manufacture Or are they sterilizer parameters There may be some indication in some of the older suppliers manuals which expand their recommendations along the lines of sterilize by autoclaving at 15psi (121°C) for 15-18min. Since pressures of 15psi are not achievable within media, it is clear that the intention was that the recommendations be applied to sterilizer parameters. 

For other materials (for instance, equipment and supplies for aseptic manufacture) where the mechanisms of inactivation rely on direct contact between the steam and the item being sterilized and therefore where air removal is matter of importance, the choice of substrate for Bis generally lies between using commercially available paper spore strips and the material itself The decision tree in 4 may be helpful. Regulatory pressure is currently toward use of inoculated product, but commercially available spore strips are more convenient. Tailor-made inoculated product requires substantial amounts of microbiological expertise. The decision tree in Fig. 4 may be helpful in selecting which approach is best in particular circumstances. 

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. 

When an ophthalmic ointment is manufactured, all raw material components must be rendered sterile before compounding unless the ointment contains an aqueous fraction that can be sterilized by heat, filtration, or ionizing radiation. The ointment base is sterilized by heat and appropriately filtered while molten to remove extraneous foreign particulate matter. It is then placed into a sterile steam-jacketed kettle to maintain the ointment in a molten state under aseptic conditions, and the previously sterilized active ingredients) and excipients are added aseptically. While still molten, the entire ointment may be passed through a previously sterilized colloid mill for adequate dispersion of the insoluble components. 

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). 

Some sterile powder formulations (these are predominantly, but not exclusively, antibiotics) may require sampling, mixing, milling, and subdivision activities similar to those found in oral powder manufacturing. The facilities and equipment utilized for these products is substantially different from that used for liquids, and the production area bears little resemblance to that utilized for liquids. These materials are received sterile and must be processed through sterilized equipment specifically intended for powder handling in a fully aseptic environment with ISO 5 protection over all open container activities. 

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