Terminal sterilization Both the FDA guidance on aseptic filling (2004) and the European Pharmacopoeia (in Chapter 5.1.1) state that of the methods of sterile manufacture a process in which the product is sterilized in its final container (terminal sterilization) is the preferred method. This is not possible for all types of products and for this filtration through a bacteria-retentive filter and aseptic processing is used.
Terminal sterilization involves filling and sealing product containers under high-quality environmental conditions. This means that non-parenteral products that are to be terminally sterilized may be filled in an EU GMP Grade C/ISO 14644 class 8 area (for detail of cleanroom grades, see Chapter 16). With parenteral products these can be filled under the same conditions if the process or product does not pose a high-
risk of microbial contamination. Examples of high-risk situations include slow-filling operations, the use of wide-necked containers or the exposure of filled containers to the environment for more than a few seconds before sealing. In these cases, products are filled in an aseptic area with at least an EU GMP Grade B/ISO 14644 class 7
environments or in an EU GMP Grade A/ISO 14644 class 5 zone with at least a Grade C/ISO class 8 background, prior to terminal sterilization. Products are filled and sealed in this type of environment to minimize the microbiological content of the in-process product and to help ensure that the subsequent steril-
ization process is successful. It is accepted that the product, container, and closure will probably have low bioburden, but they are not sterile. The product in its final container is then subjected to a terminal sterilization process such as heat or irradiation. As terminally sterilized drug product, each product unit undergoes a single sterilization process in a sealed container. The assumption is that the bioburden within the product can be eliminated by the sterilization process selected . Product formulation is undertaken at an EU GMP Grade C/ISO 14644 class 8 or an EU GMP Grade D/ISO 14644 class 9 environment. For some higher risk products a pre-filtration through a bacteria-retentive filter may be advisable in cases, particularly where there is a high bioburden. It is up to the pharmaceutical organization to define
the level of risk and to justify this to an inspector.
Aseptic manufacturing is used in cases where the drug substance is instable when subjected to heat (thus, sterilization in the final container closure system is not possible) or where heat would cause packaging degradation. Aseptic filling is arguably
the most difficult type of sterile operations. This is because the end product cannot be terminally sterilized and, therefore, there are far greater contamination risks during formulation and filling. With aseptic processing, there is always a degree of uncertainty, particularly because of the risk posed by personnel to the environment in which
filling takes place. In aseptic manufacture, the dosage form and the individual components of the con-
tainments system are sterilized separately, and then the whole presentation is brought together by methods that ensure that the existing sterility is not compromised. Sterility
is normally achieved through sterile filtration of the bulk using a sterilizing grade filter (with a pore size of 0.2μm or smaller) in sterile container closure systems and working in a clean area . This is undertaken in an EU GMP Grade C/ISO 14644 class 8 cleanroom environment. The container and closure are also subject to sterilization methods separately. The sterilized bulk product is filled into the containers, stoppered
and sealed under aseptic conditions (under EU GMP Grade A/ISO 14644 class 5 air) within an EU GMP Grade B/ISO 14644 class 7 cleanroom, unless filling is undertaken within a barrier system.
To assist with aseptic processing, engineering and manufacturing technology throughout all industries have evolved considerably. In the context of sterile and aseptic manufacture of pharmaceutical and medical devices, blow-fill-seal (BFS), prefilled syringe filling, restricted access barrier systems (RABS), and isolator technologies represent the main developments. Aseptic processes that exclude human intervention (such as robotics or barrier systems) are at a considerably lower risk than operations that consist of filling machines under unidirectional airflow devices where there is a need for periodic human intervention. With isolator systems the background Designing of aseptic area, laminar flow equipments; study of different sources of contamination in an aseptic area and methods of prevention, clean area classification. Principles and methods of different microbiological assay. Methods for standardization of antibiotics, vitamins and amino acids. Assessment of a new antibiotic.