Aseptic manufacture

Because of these product sensitivities, most ophthalmic pharmaceutical products are aseptically manufactured and filled into previously sterilized containers in aseptic environments using aseptic filling-and-capping techniques. This is the case for ophthalmic solutions, suspensions, and ointments, and specialized technology is involved in their manufacture. 

Two types of compressed air systems are found in an aseptic manufacturing facility ... 

Three vacuum systems are commonly used in modern aseptic manufacturing facilities (1) house vacuum systems, (2) vacuum systems dedicated to lyophilization equipment, and (3) vacuum systems dedicated to autoclaves or other sterilization equipment. 

Laminar flow sterilization tunnels are widely used in high-speed aseptic manufacturing. Typically, laminar flow tunnels contain three sections (1) preheating, (2) heating, and (3) cooling. 

Five discrete cleaning validation protocols related to aseptic manufacturing equipments, solution preparation tanks, mobile tanks, filtration assemblies, freeze dryers, and vial filling machine parts are provided in Section Val. 2200. 

Non-aseptic manufacture and packing Aseptic manufacture and packing... 

Product quality is critically affected by BMS control and monitoring for aseptic manufacturing such as parenterals. Reliance on alarming out-of-specification environment conditions is insufficient to support high integrity product. Independent monitoring does not relieve the basic reliance on BMS operability and should therefore be validated. 

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. 

The range of sterilization specifications calculable by these various approaches is summarized in Table 2. It is apparent that very brief sterilization specifications (on the order of 2-3 min holding time at 121°C) are obtainable when the microbiological contamination is completely characterized in terms of numbers and thermal resistances. In practice, such limits on hold times could be difficult to control precisely, are probably insignificant in terms of thermal lethality compared with heat-up and cool-down times, and could prove difficult to sell to regulators. Without complete thermal characterization of thermal resistances, specifications calculable by the bioburden approach are hardly significantly shorter than overkill specifications. Thus, it probably makes practical sense in most cases to choose only between overkill cycles for thermally resistant products and aseptic manufacture for heat-sensitive products. 

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. 

BFS machinery and associated equipment for aseptic manufacture should be constructed in such a way that the product pathways are of hygienic design with hygienic valves and minimal joints to facilitate cleaning and sterilizing in place. 

Broth fills should be carried out under conditions that are representative of those during normal operation. If there is to be a deviation from routine processes, it should only be in the direction of presenting a greater, rather than a lesser, challenge to the process. Due to the level of automation of BFS technology, it is extremely difficult to take extra care in order to reduce the chance of container contamination during a broth fill therefore, results are not as operator-dependent as other less automated aseptic manufacturing processes. 

Validation is described as proof that the system performs as stated. As an engineering control, the LAF system must demonstrably support the intended aseptic or controlled process. Validation of the aseptic manufacturing process and the LAF systems that support terminal sterilization in pharmaceutical manufacturing applications should be carried out in accordance with industry standards. Such validation should be accomplished in three phases, consisting of installation qualification (IQ), operational qualification (OQ), and process qualification (PQ), with full and detailed documentation of all activities and... 

Use in the production of vaccines As assay organisms to determine antibiotic, vitamin and amino acid concentrations Quality control of immunological products Assay methods Sterilization methods Sterilization monitoring and validation procedures Sterility testing Assessment and calculation of sterility assurance Aseptic manufacture... 

Blow/fill/seal units are purpose-built pieces of equipment, which carry out these three steps in a continuous process within a controlled environment. Containers, which are formed from thermoplastic granules, are blown to form the correct shape, filled and heat-sealed. These units are fitted with a grade A air shower and operated in a grade C environment for aseptic manufacture and a grade D background for products which are to be terminally sterilized. 

---